Morpholine-spirocyclic piperidine amides as modulators of ion channels

ABSTRACT

The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/418,737, filed Mar. 13, 2012, the entire contents of which isincorporated herein by reference. U.S. application Ser. No. 13/418,737,claims priority to U.S. provisional patent application Ser. Nos.61/452,538, filed Mar. 14, 2011, and 61/567,809, filed Dec. 7, 2011, theentire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of ion channels.The invention also provides pharmaceutically acceptable compositionscomprising the compounds of the invention and methods of using thecompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Voltage-gated sodium channels are believed to play a critical role inpain signaling. This belief is based on the known roles of thesechannels in normal physiology, pathological states arising frommutations in sodium channel genes, preclinical work in animal models ofdisease, and the clinical usefulness of known sodium channel modulatingagents (Cummins, T. R., Sheets, P. L., and Waxman, S. G., The roles ofsodium channels in nociception: Implications for mechanisms of pain.Pain 131 (3), 243 (2007); England, S., Voltage-gated sodium channels:the search for subtype-selective analgesics. Expert Opin Investig Drugs17 (12), 1849 (2008); Krafte, D. S, and Bannon, A. W., Sodium channelsand nociception: recent concepts and therapeutic opportunities. CurrOpin Pharmacol 8 (1), 50 (2008)).

Voltage-gated sodium channels (NaV's) are key biological mediators ofelectrical signaling. NaV's are the primary mediators of the rapidupstroke of the action potential of many excitable cell types (e.g.neurons, skeletal myocytes, cardiac myocytes), and thus are critical forthe initiation of signaling in those cells (Hille, Bertil, Ion Channelsof Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland,Mass., 2001)). Because of the role NaV's play in the initiation andpropagation of neuronal signals, antagonists that reduce NaV currentscan prevent or reduce neural signaling. Thus NaV channels are consideredlikely targets in pathologic states where reduced excitability ispredicted to alleviate the clinical symptoms, such as pain, epilepsy,and some cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, O.,and Krupp, J. J., Voltage-gated sodium channels in neurologicaldisorders. CNS Neurol Disord Drug Targets 7 (2), 144 (2008)).

The NaV's form a subfamily of the voltage-gated ion channel super-familyand comprises 9 isoforms, designated NaV 1.1-NaV 1.9. The tissuelocalizations of the nine isoforms vary greatly. NaV 1.4 is the primarysodium channel of skeletal muscle, and NaV 1.5 is primary sodium channelof cardiac myocytes. NaV's 1.7, 1.8 and 1.9 are primarily localized tothe peripheral nervous system, while NaV's 1.1, 1.2, 1.3, and 1.6 areneuronal channels found in both the central and peripheral nervoussystems. The functional behaviors of the nine isoforms are similar butdistinct in the specifics of their voltage-dependent and kineticbehavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G.,International Union of Pharmacology. XLVII. Nomenclature andstructure-function relationships of voltage-gated sodium channels.Pharmacol Rev 57 (4), 397 (2005)).

NaV channels have been identified as the primary target for someclinically useful pharmaceutical agents that reduce pain (Cummins, T.R., Sheets, P. L., and Waxman, S. G., The roles of sodium channels innociception: Implications for mechanisms of pain. Pain 131 (3), 243(2007)). The local anesthetic drugs such as lidocaine block pain byinhibiting NaV channels. These compounds provide excellent local painreduction but suffer the drawback of abolishing normal acute pain andsensory inputs. Systemic administration of these compounds results indose limiting side effects that are generally ascribed to block ofneural channels in the CNS (nausea, sedation, confusion, ataxia).Cardiac side effects can also occur, and indeed these compounds are alsoused as class 1 anti-arrhythmics, presumably due to block of NaV1.5channels in the heart. Other compounds that have proven effective atreducing pain have also been suggested to act by sodium channel blockadeincluding carbamazepine, lamotragine, and tricyclic antidepressants(Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur J Pain 6 Suppl A, 3 (2002); Wang, G. K., Mitchell, J., and Wang, S.Y., Block of persistent late Na⁺ currents by antidepressant sertralineand paroxetine. J Membr Biol 222 (2), 79 (2008)). These compounds arelikewise dose limited by adverse effects similar to those seen with thelocal anesthetics. Antagonists that specifically block only theisoform(s) critical for nocioception are expected to have increasedefficacy since the reduction of adverse effects caused by block ofoff-target channels should enable higher dosing and thus more completeblock of target channels isoforms.

Four NaV isoforms, NaV 1.3, 1.7, 1.8, and 1.9, have been specificallyindicated as likely pain targets. NaV 1.3 is normally found in the painsensing neurons of the dorsal root ganglia (DRG) only early indevelopment and is lost soon after birth both in humans and in rodents.Nonetheless, nerve damaging injuries have been found to result in areturn of the NaV 1.3 channels to DRG neurons and this may contribute tothe abnormal pain signaling in various chronic pain conditions resultingfrom nerve damage (neuropathic pain). These data have led to thesuggestion that pharmaceutical block of NaV 1.3 could be an effectivetreatment for neuropathic pain. In opposition to this idea, globalgenetic knockout of NaV 1.3 in mice does not prevent the development ofallodynia in mouse models of neuropathic pain (Nassar, M. A. et al.,Nerve injury induces robust allodynia and ectopic discharges in NaV 1.3null mutant mice. Mol Pain 2, 33 (2006)). It remains unknown whethercompensatory changes in other channels allow for normal neuropathic painin NaV 1.3 knockout mice, though it has been reported that knockout ofNaV 1.1 results in drastic upregulation of NaV 1.3. The converse effectin NaV 1.3 knockouts might explain these results.

NaV 1.7, 1.8, and 1.9 are highly expressed in DRG neurons, including theneurons whose axons make up the C-fibers and Aδ nerve fibers that arebelieved to carry most pain signals from the nocioceptive terminals tothe central nervous. Like NaV 1.3, NaV 1.7 expression increases afternerve injury and may contribute to neuropathic pain states. Thelocalization of NaV 1.7, 1.8, and 1.9 in nocioceptors led to thehypothesis that reducing the sodium currents through these channelsmight alleviate pain. Indeed, specific interventions that reduce thelevels of these channels have proven effective in animal models of pain.

Specific reduction of NaV 1.7 in rodents by multiple differenttechniques has resulted in the reduction of observable pain behaviors inmodel animals. Injection of a viral antisense NaV 1.7 cDNA constructgreatly reduces normal pain responses due to inflammation or mechanicalinjury (Yeomans, D. C. et al., Decrease in inflammatory hyperalgesia byherpes vector-mediated knockdown of NaV 1.7 sodium channels in primaryafferents. Hum Gene Ther 16 (2), 271 (2005)). Likewise, a geneticknockout of NaV 1.7 in a subset of nociceptor neurons reduced acute andinflammatory pain in mouse models (Nassar, M. A. et al.,Nociceptor-specific gene deletion reveals a major role for NaV 1.7 (PN1)in acute and inflammatory pain. Proc Natl Acad Sci USA 101 (34), 12706(2004)). Global knockouts of NaV 1.7 in mice lead to animals that die onthe first day after birth. These mice fail to feed and this is thepresumed cause of death.

Treatments that specifically reduce NaV 1.8 channels in rodent modelseffectively reduce pain sensitivity. Knockdown of NaV 1.8 in rats byintrathecal injection of antisense oligodeoxynucleotides reducesneuropathic pain behaviors, while leaving acute pain sensation intact(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Porreca, F. et al., A comparison of the potential role of thetetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in ratmodels of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640 (1999)).Global genetic knockout of NaV 1.8 in mice or specific destruction ofNaV 1.8 expressing neurons greatly reduces perception of acutemechanical, inflammatory, and visceral pain (Akopian, A. N. et al., Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways. Nat Neurosci 2 (6), 541 (1999); Abrahamsen, B. et al.,The cell and molecular basis of mechanical, cold, and inflammatory pain.Science 321 (5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N.,and Cervero, F., Deficits in visceral pain and referred hyperalgesia inNaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)). Incontrast to the antisense experiments in rats, genetic knockout miceappear to develop neuropathic pain behaviors normally after nerve injury(Lai, J. et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143(2002); Akopian, A. N. et al., The tetrodotoxin-resistant sodium channelSNS has a specialized function in pain pathways. Nat Neurosci 2 (6), 541(1999); Abrahamsen, B. et al., The cell and molecular basis ofmechanical, cold, and inflammatory pain. Science 321 (5889), 702 (2008);Laird, J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits invisceral pain and referred hyperalgesia in NaV 1.8 (SNS/PN3)-null mice.J Neurosci 22 (19), 8352 (2002)).

NaV 1.9 global knock out mice have decreased sensitivity to inflammationinduced pain, despite normal acute, and neuropathic pain behaviors(Amaya, F. et al., The voltage-gated sodium channel Na(v)1.9 is aneffector of peripheral inflammatory pain hypersensitivity. J Neurosci 26(50), 12852 (2006); Priest, B. T. et al., Contribution of thetetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensorytransmission and nociceptive behavior. Proc Natl Acad Sci USA 102 (26),9382 (2005)). Spinal knockdown of NaV 1.9 had no apparent effect on painbehavior in rats (Porreca, F. et al., A comparison of the potential roleof the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2,in rat models of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640(1999)).

The understanding of the role of NaV channels in human physiology andpathology has been greatly advanced by the discovery and analysis ofnaturally occurring human mutations. NaV 1.1 and NaV 1.2 mutationsresult in various forms of epilepsy (Fujiwara, T., Clinical spectrum ofmutations in SCN1A gene: severe myoclonic epilepsy in infancy andrelated epilepsies. Epilepsy Res 70 Suppl 1, S223 (2006); George, A. L.,Jr., Inherited disorders of voltage-gated sodium channels. J Clin Invest115 (8), 1990 (2005); Misra, S, N., Kahlig, K. M., and George, A. L.,Jr., Impaired NaV1.2 function and reduced cell surface expression inbenign familial neonatal-infantile seizures. Epilepsia 49 (9), 1535(2008)). Mutations of the NaV 1.4 cause muscular disorders likeparamyotonia congenital (Vicart, S., Sternberg, D., Fontaine, B., andMeola, G., Human skeletal muscle sodium channelopathies. Neurol Sci 26(4), 194 (2005)). NaV 1.5 mutations result in cardiac abnormalities likeBrugada Syndrome and long QT syndrome (Bennett, P. B., Yazawa, K.,Makita, N., and George, A. L., Jr., Molecular mechanism for an inheritedcardiac arrhythmia. Nature 376 (6542), 683 (1995); Darbar, D. et al.,Cardiac sodium channel (SCN5A) variants associated with atrialfibrillation. Circulation 117 (15), 1927 (2008); Wang, Q. et al., SCN5Amutations associated with an inherited cardiac arrhythmia, long QTsyndrome. Cell 80 (5), 805 (1995)).

Recent discoveries have demonstrated that mutations in the gene thatencodes the NaV 1.7 channel (SCN9A) can cause both enhanced and reducedpain syndromes. Work by Waxman's group and others have identified atleast 15 mutations that result in enhanced current through NaV 1.7 andare linked to dominant congenital pain syndromes. Mutations that lowerthe threshold for NaV 1.7 activation cause inherited erythromelalgia(IEM). IEM patients exhibit abnormal burning pain in their extremities.Mutations that interfere with the normal inactivation properties of NaV1.7 lead to prolonged sodium currents and cause paroxysmal extreme paindisorder (PEPD). PEPD patients exhibit periocular, perimandibular, andrectal pain symptoms that progresses throughout life (Drenth, J. P. etal., SCN9A mutations define primary erythermalgia as a neuropathicdisorder of voltage gated sodium channels. J Invest Dermatol 124 (6),1333 (2005); Estacion, M. et al., NaV 1.7 gain-of-function mutations asa continuum: A1632E displays physiological changes associated witherythromelalgia and paroxysmal extreme pain disorder mutations andproduces symptoms of both disorders. J Neurosci 28 (43), 11079 (2008)).

NaV 1.7 null mutations in human patients were recently described byseveral groups (Ahmad, S. et al., A stop codon mutation in SCN9A causeslack of pain sensation. Hum Mol Genet. 16 (17), 2114 (2007); Cox, J. J.et al., An SCN9A channelopathy causes congenital inability to experiencepain. Nature 444 (7121), 894 (2006); Goldberg, Y. P. et al.,Loss-of-function mutations in the NaV 1.7 gene underlie congenitalindifference to pain in multiple human populations. Clin Genet. 71 (4),311 (2007)). In all cases patients exhibit congenital indifference topain. These patients report no pain under any circumstances. Many ofthese patients suffer dire injuries early in childhood since they do nothave the protective, normal pain that helps to prevent tissue damage anddevelop appropriate protective behaviors. Aside from the striking lossof pain sensation and reduced or absent of smell (Goldberg, Y. P. etal., Loss-of-function mutations in the NaV 1.7 gene underlie congenitalindifference to pain in multiple human populations. Clin Genet. 71 (4),311 (2007)), these patients appear completely normal. Despite thenormally high expression of NaV 1.7 in sympathetic neurons (Toledo-Aral,J. J. et al., Identification of PN1, a predominant voltage-dependentsodium channel expressed principally in peripheral neurons. Proc NatlAcad Sci USA 94 (4), 1527 (1997)) and adrenal chromafin cells(Klugbauer, N., Lacinova, L., Flockerzi, V., and Hofmann, F., Structureand functional expression of a new member of the tetrodotoxin-sensitivevoltage-activated sodium channel family from human neuroendocrine cells.EMBO J. 14 (6), 1084 (1995)), these NaV 1.7-null patients show no signof neuroendocrine or sympathetic nervous dysfunction.

The gain of NaV 1.7 function mutations that cause pain, coupled with theloss of NaV 1.7 function mutations that abolish pain, provide strongevidence that NaV 1.7 plays an important role in human pain signaling.The relative good health of NaV 1.7-null patients indicates thatablation of NaV 1.7 is well tolerated in these patients.

Unfortunately, the efficacy of currently used sodium channel blockersfor the disease states described above has been to a large extentlimited by a number of side effects. These side effects include variousCNS disturbances such as blurred vision, dizziness, nausea, and sedationas well more potentially life threatening cardiac arrhythmias andcardiac failure. Accordingly, there remains a need to develop additionalNa channel antagonists, preferably those with higher potency and fewerside effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein, independently for each occurrence:

-   R¹ is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, halo, CN,    NR⁸SO₂R⁸, SO₂R⁸, SR⁸, SOR⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂,    CF₃, optionally substituted heterocycloalkyl, phenyl, heteroaryl, or    a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two    CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸, or    two R¹ taken together form an oxo group;-   R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, CF₃, optionally substituted    cycloalkyl, aryl, heteroaryl or heterocycloalkyl, COR⁸, CO₂R⁸,    CON(R⁸)₂, CF₃, CHF₂, or a straight chain, branched, or cyclic    (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO,    S, SO, SO₂, N, CF₂, or NR⁸;-   R³ is C1-C6 alkyl or halo;-   R⁸ is H, C1-C6 alkyl, or C3-C8 cycloalkyl, a straight chain,    branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be    replaced with O, CO, S, SO, SO₂, N, CF₂, or NR, or 2 R⁸ taken    together with the atoms to which they are attached form a ring;-   R⁹ is H, CF₃, CHF₂, CH₂F, CO₂R, OH, optionally substituted aryl,    heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R)₂, NRCOR,    CON(R)₂, CN, or SO₂R;-   R is H, C1-C6 alkyl, optionally substituted aryl, heteroaryl, C3-C8    cycloalkyl, or heterocycloalkyl;-   A is an optionally substituted aryl, heteroaryl or heterocyclic;-   n is an integer from 0 to 4 inclusive; and-   o is an integer from 0 to 4 inclusive.

In a further embodiment, R¹ is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C8cycloalkyl, CN, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, optionally substitutedheterocycloalkyl, phenyl, heteroaryl, or a straight chain, branched, orcyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O,CO, S, SO, SO₂, N, CF₂, or NR⁸, or two R¹ taken together form an oxogroup.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. The phrase “optionally substituted” isused interchangeably with the phrase “substituted or unsubstituted.” Asdescribed herein, the variables R¹-R⁹ in formula I encompass specificgroups, such as, for example, alkyl and aryl. Unless otherwise noted,each of the specific groups for the variables R¹-R⁸ can be optionallysubstituted with one or more substituents of halo, cyano, oxoalkoxy,hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, analkyl group can be optionally substituted with one or more of halo,cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. Asan additional example, an aryl group can be optionally substituted withone or more of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, andalkyl. As one of ordinary skill in the art will recognize, combinationsof substituents envisioned by this invention are those combinations thatresult in the formation of stable or chemically feasible compounds. Theterm “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week. When two alkoxy groups are bound to thesame atom or adjacent atoms, the two alkoxy groups can form a ringtogether with the atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3. The term “aliphatic”,“aliphatic group” or “alkyl” as used herein, means a straight-chain(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbonchain that is completely saturated or that contains one or more units ofunsaturation. Unless otherwise specified, aliphatic groups contain 1-20aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-10 aliphatic carbon atoms. In other embodiments, aliphatic groupscontain 1-8 aliphatic carbon atoms. In still other embodiments,aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet otherembodiments aliphatic groups contain 1-4 aliphatic carbon atoms.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.The term “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbon,bicyclic, or tricyclic hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromaticand has a single point of attachment to the rest of the molecule. Insome embodiments, “cycloaliphatic” refers to a monocyclic C₃-C₈hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completely saturatedor that contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members.

The term “electron withdrawing group”, as used herein means an atom or agroup that is electronegative relative to hydrogen. See, e.g., “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure,” Jerry March,4^(th) Ed., John Wiley & Sons (1992), e.g., pp. 14-16, 18-19, etc.Exemplary such substituents include halo such as Cl, Br, or F, CN, COOH,CF₃, etc.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, “heterocycloalkyl” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”,“heterocycloalkyl” or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Thus, included withinthe scope of the invention are tautomers of compounds of formula I.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds of formulaI, wherein one or more hydrogen atoms are replaced deuterium or tritium,or one or more carbon atoms are replaced by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools, probes in biological assays,or sodium channel blockers with improved therapeutic profile.

In the formulas and drawings, a line transversing a ring and bonded toan R group such as in

means that the R group can be bonded to any carbon, or if applicable,heteroatom such as N, of that ring as valency allows.

Within a definition of a term as, for example, R¹, R²R³, R⁴, R⁵, or R⁶when a CH₂ unit or, interchangeably, methylene unit may be replaced byO, CO, S, SO, SO₂ or NR⁸, it is meant to include any CH₂ unit, includinga CH₂ within a terminal methyl group. For example, —CH₂CH₂CH₂SH iswithin the definition of C1-C6 alkyl wherein up to two CH₂ units may bereplaced by S because the CH₂ unit of the terminal methyl group has beenreplaced by S.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R¹ is halo or optionallysubstituted aryl, heteroaryl, C1-C6 alkyl, C1-C6 fluoroalkyl, a straightchain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may bereplaced with O, CO, S, SO, SO₂, N, or NR⁸, or 2 R¹ taken together forman oxo group. In another embodiment, R¹ is F or optionally substitutedphenyl, pyridyl, oxazole, thiazole, pyrazole, oxadiazole, CH₂OCH₃, CH₂F,CH₂OCH(CH₃)₂, CH₂OCHF₂, CH₃, CH₂CH₃, CH₂OH, C(CH₃)₂OH, CH₂CH₂OH,CH₂OCH₂CH₃, CH(CH₂)₂,

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is H, C1-C6 alkyl, C1-C6fluoroalkyl, CF₃, an optionally substituted cycloalkyl, aryl,heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic(C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S,SO, SO₂, N, or NR⁸. In another embodiment, R² is H, CH₂CHF₂, CH₂CF₃,CH(CH₃)CH₂F, CH₂CH(CH₃)₂, CH₃, CH₂CH₃, tBu, CH₂CN, CH(CH₃)₂,CH(CH₂CH₃)₂, CH₂C(CH₃)₂OH, CH₂CH₂CH(CH₃)₂, CH₂CH₂OH, C(O)CH₃,C(O)CH₂CH₃, C(O)CH(CH₃)₂, CH₂CF₂CH₃, CH₂CCCH₃, CH₂C(O)tBu, CH₂CH₂OCH₃,CH₂OCH₃, CH₂C(O)CH₃, CH₂C(O)OCH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂CCCH₂CH₃,CH₂CH₂OCH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂CH₂OCH₃, CH₂CH(CH₂CH₃)₂, n-butyl,n-propyl,

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein n is 0, 1, 2, or 3. In anotherembodiment, n is 1 or 2. In another embodiment, n is 1.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein o is 0 or 1. In anotherembodiment, o is 0.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein A is

wherein:

-   R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸,    CON(R⁸)₂, SO₂N(R⁸)₂, CHF₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl,    heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched,    or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8    cycloalkoxy, halo, CN, OH, OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸,    CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹,    heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight    chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units    may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸,    CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl,    heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched,    or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; or-   two occurrences of R⁴ and R⁵, or R⁵ and R⁶ together with the carbons    to which they are attached form an optionally substituted ring    comprising up to 2 heteroatoms.

In another embodiment, R⁴ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, OCF₃,OCHF₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up tothree CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁷. Inanother embodiment, R⁴ is H, F, CH₃, OCH₃, OCF₃, or OCHF₂.

In another embodiment, R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF₃,CN, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up tothree CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸. Inanother embodiment, R⁵ is H, CH₃, OCH₃, OCH₂CH₃, OCH(CH₃)₂, F, Cl, CN,CF₃, or CH₂OH.

In another embodiment, R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, SO₂R⁸,SO₂N(R⁸)₂, R⁹, or a straight chain, branched, or cyclic (C1-C8)-R⁹,wherein up to three CH₂ units may be replaced with O, S, SO, SO₂, N, orNR⁸. In another embodiment, R⁶ is H, CH₂OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,OCH₂CH₂CH(CH₃)₂, OtBu, tBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃, CH(OH)CH(CH₃)₂,C(OH)(CH₂CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH,OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃,SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein

is selected from:

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein A is heteroaryl or heterocyclic.In another embodiment, A is a monocyclic heteroaryl comprising 1 to 3heteroatoms independently selected from N, O, or S. In anotherembodiment, A is selected from a bicyclic heteroaryl comprising from 1to 3 heteroatoms independently selected from N, O, or S.

In another embodiment, A is

wherein:

-   R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸,    CON(R⁸)₂, SO₂N(R⁸)₂, CHF₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl,    heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched,    or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8    cycloalkoxy, halo, CN, OH, OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸,    CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹,    heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight    chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units    may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸,    CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl,    heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched,    or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced    with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; or    two occurrences of R⁴ and R⁵, or R⁵ and R⁶ together with the carbons    to which they are attached form an optionally substituted ring    comprising up to 2 heteroatoms.

In another embodiment, R⁴ is H or C1-C6 alkyl. In another embodiment, R⁴is H.

In another embodiment, R⁵ is H, C1-C6 alkyl, or C1-C6 alkoxy. In anotherembodiment, R⁵ is H, CH₃, or OCH₃.

In another embodiment, R⁶ is H, CN, C1-C6 alkoxy, or CF₃. In anotherembodiment, R⁶ is H, CN, OCH₃, or CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein A is selected from the following:

In another embodiment, the invention features the compounds of formula Iand the attendant definitions, wherein the compound has formula IA:

wherein:

-   R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted    cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or a straight    chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units    may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, halo, CF₃,    OCF₃, OCHF₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, SO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂,    heterocycloalkyl, or a straight chain, branched, or cyclic    (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO,    S, SO, SO₂, N, CF₂, or NR⁸;-   R⁷ is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, CF₃, OCF₃, or OCHF₂; and-   p is an integer from 0 to 3 inclusive.

In another embodiment, R² is selected from C1-C6 alkyl, C1-C6fluoroalkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In anotherembodiment, R² is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CHF₂, CH₂CF₃,CH(CH₃)CH₂F, CH₂CN, CH₂CH₂OH, CH₂C(CH₃)₂OH, COCH₂CH₃, or COCH(CH₃)₂.

In another embodiment, R⁵ is selected from H, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 fluororoalkyl, halo, or a straight chain, branched, or cyclic(C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, N, CF₂, or NR⁸. In another embodiment, R⁵ is H, CH₃, OCH₃,OCH₂CH₃, CF₃, Cl, F, or CH₂OH.

In another embodiment, R⁶ is selected from H, C1-C6 alkoxy, or astraight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In anotherembodiment, R⁶ is H, CH₂OH, OCH₂CH₃, OtBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃,CH(OH)CH(CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH,OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃,SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

In another embodiment, R⁷ is halo. In another embodiment, R⁷ is F.

In another embodiment, the

moiety is selected from:

In another embodiment, the invention features a compound of formula Iand the attendant definitions of the above embodiments, wherein thecompound has formula IB:

wherein:

-   R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted    cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, or a straight    chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units    may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, halo, CF₃,    OCF₃, OCHF₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹    wherein up to three CH₂ units may be replaced with O, CO, S, SO,    SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, SO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂,    heterocycloalkyl, or a straight chain, branched, or cyclic    (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO,    S, SO, SO₂, N, CF₂, or NR⁸;-   R⁷ is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, CF₃, OCF₃, or OCHF₂; and-   p is an integer from 0 to 3 inclusive.

In another embodiment, R² is selected from C1-C6 alkyl, C1-C6fluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or astraight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In anotherembodiment, R² is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CHF₂, CH₂CF₃,CH(CH₃)CH₂F, CH₂CN, CH₂CH₂OH, CH₂C(CH₃)₂OH, COCH₂CH₃, or COCH(CH₃)₂.

In another embodiment, R⁵ is selected from H, C1-C6 alkyl, C1-C6 alkoxy,C1-C6 fluororoalkyl, halo, or a straight chain, branched, or cyclic(C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S,SO, SO₂, N, CF₂, or NR⁸. In another embodiment, R⁵ is H, CH₃, OCH₃,OCH₂CH₃, CF₃, Cl, F, or CH₂OH.

In another embodiment, R⁶ is selected from H, C1-C6 alkoxy, or astraight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In anotherembodiment, R⁶ is H, CH₂OH, OCH₂CH₃, OtBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃,CH(OH)CH(CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH,OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃,SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

In another embodiment, R⁷ is halo. In another embodiment, R⁷ is F.

In another embodiment, the

moiety is selected from:

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein the compound has formula IC:

wherein,

-   the Het ring is a mono or bicyclic optionally substituted    heterocyclic or heteroaryl ring;-   R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted    aryl, heteroaryl, or heterocycloalkyl, or a straight chain,    branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be    replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF₃, OCF₃, OCHF₂, or a    straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three    CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, SO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂,    heterocycloalkyl, or a straight chain, branched, or cyclic    (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO,    S, SO, SO₂, N, CF₂, or NR⁸-   R⁷ is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, CF₃, OCF₃, or OCHF₂; and-   p is an integer from 0 to 3 inclusive.

In another embodiment, the Het ring is an optionally substitutedthiazole, pyridine, pyrazole, oxazole, or oxadiazole.

In another embodiment, p is 0 or 1.

In another embodiment, R⁷ is C1-C6 alkyl.

In another embodiment, R⁷ is CH₃, CH₂CH₃, CH(CH₃)₂, or tBu.

In another embodiment, the Het ring is

In another embodiment, R² is selected from C1-C6 alkyl or a straightchain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may bereplaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In another embodiment,R² is CH₂CH₃, tBu, CH₂CHF₂, CH₂CF₃, or

In another embodiment, R⁵ is selected from H, C1-C6 alkyl, C1-C6 alkoxy,or halo. In another embodiment, R⁵ is H, CH₃, OCH₃, F, or Cl.

In another embodiment, R⁶ is H, C1-C6 alkoxy, or a straight chain,branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In another embodiment,R⁶ is OCH(CH₃)₂, C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH,

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein the compound has formula ID:

wherein,

-   the Het ring is a mono or bicyclic optionally substituted    heterocyclic or heteroaryl ring;-   R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted    aryl, heteroaryl, or heterocycloalkyl, or a straight chain,    branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be    replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF₃, OCF₃, OCHF₂, or a    straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three    CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸;-   R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, CN, SO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂,    heterocycloalkyl, or a straight chain, branched, or cyclic    (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO,    S, SO, SO₂, N, CF₂, or NR⁸-   R⁷ is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH,    OR⁸, N(R⁸)₂, CF₃, OCF₃, or OCHF₂; and-   p is an integer from 0 to 3 inclusive.

In another embodiment, the Het ring is an optionally substitutedthiazole, pyridine, pyrazole, oxazole, or oxadiazole.

In another embodiment, p is 0 or 1.

In another embodiment, R⁷ is C1-C6 alkyl.

In another embodiment, R⁷ is CH₃, CH₂CH₃, CH(CH₃)₂, or tBu.

In another embodiment, the Het ring is

In another embodiment, R² is selected from C1-C6 alkyl or a straightchain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may bereplaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In another embodiment,R² is CH₂CH₃, tBu, CH₂CHF₂, CH₂CF₃, or

In another embodiment, R⁵ is selected from H, C1-C6 alkyl, C1-C6 alkoxy,or halo. In another embodiment, R⁵ is H, CH₃, OCH₃, F, or Cl.

In another embodiment, R⁶ is H, C1-C6 alkoxy, or a straight chain,branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may bereplaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸. In another embodiment,R⁶ is OCH(CH₃)₂, C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH,

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein the compound is selected from thefollowing table:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium ion channel in:

a patient; or

a biological sample;

comprising administering to the patient, or contacting the biologicalsample, with a compound or composition of the invention. In anotherembodiment, the voltage-gated sodium ion channel is NaV 1.7.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders, anxiety,depression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, cancer pain, stroke, cerebralischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-or exercise induced angina, palpitations, hypertension, migraine, orabnormal gastro-intestinal motility, comprising administering aneffective amount of a compound or composition of the invention.

In another embodiment, the method is used for treating or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic; IBS pain; chronic and acute headache pain;migraine; tension headache, including, cluster headaches; chronic andacute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain, abdominal pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn and trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain including sinusitis pain, dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet's diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry'sdisease pain; bladder and urogenital disease, including, urinaryincontinence; hyperactivity bladder; painful bladder syndrome;interstitial cyctitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I and type II; widespread pain, paroxysmal extreme pain,pruritis, tinnitis, or angina-induced pain.

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 through Scheme 21 aremethods for preparing the compounds of the invention.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the invention provides compounds that are inhibitorsof voltage-gated sodium ion channels, and thus the present compounds areuseful for the treatment of diseases, disorders, and conditionsincluding, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of theinvention, pharmaceutically acceptable compositions are provided,wherein these compositions comprise any of the compounds as describedherein, and optionally comprise a pharmaceutically acceptable carrier,adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method of treatment or lessening the severityof stroke, cerebral ischemia, traumatic brain injury, amyotrophiclateral sclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abnormal gastro-intestinal motility isprovided comprising administering an effective amount of a compound, ora pharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain isprovided comprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof. Incertain other embodiments, a method for the treatment or lessening theseverity of radicular pain, sciatica, back pain, head pain, or neck painis provided comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof. In still other embodiments, a method for the treatment orlessening the severity of severe or intractable pain, acute pain,postsurgical pain, back pain, tinnitis or cancer pain is providedcomprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; angina-induced painis provided, comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof.

In certain embodiments of the invention an “effective amount” of thecompound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the subject to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the invention will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “subject” or “patient”, as used herein, means an animal, preferablya mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,or NaV1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where activation orhyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.7 and/or NaV1.8.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such asNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butabital, mephobarbital, metharbital, methohexital,pentobarbital, phenobartital, secobarbital, talbutal, theamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) an Hi antagonist having a sedative action, e.g. diphenhydramine,pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex(R), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmetatomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate orvalproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-Iantagonist, e.g.([alpha]R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion(R) or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist(e.g. capsazepine);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HTi B/I Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT2A receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®;

(25) a PDEV inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-<i]pyrimidm-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-Nyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;(z) an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(26) a cannabinoid;

(27) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(28) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(29) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, buproprion, buproprion metabolitehydroxybuproprion, nomifensine and viloxazine (Vivalan(R)), especially aselective noradrenaline reuptake inhibitor such as reboxetine, inparticular (S,S)-reboxetine;

(30) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine,milnacipran and imipramine;

(31) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,5-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,5-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butylJthioJ-S-chloro-5-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, orguanidinoethyldisulfide;

(32) an acetylcholinesterase inhibitor such as donepezil;

(33) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(34) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870,

(35) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone(CV-6504);

(36) a sodium channel blocker, such as lidocaine;

(37) a 5-HT3 antagonist, such as ondansetron; and the pharmaceuticallyacceptable salts and solvates thereof.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, activity in a biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof biopsied materialobtained from a mammal or extracts thereof and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, thestudy of sodium ion channels in biological and pathological phenomena;and the comparative evaluation of new sodium ion channel inhibitors.

EXAMPLES General Methods

¹H NMR (400 MHz or 300 MHz) and ¹³C NMR (100 MHz) spectra were obtainedas solutions in deuterioacetonitrile (CD₃CN), chloroform-d (CDCl₃),deuteromethanol (MeOD-d4), or dimethyl sulfoxide-D₆ (DMSO). Mass spectra(MS) were obtained using an Applied Biosystems API EX LC/MS systemequipped with a Phenomenex 50×4.60 mm luna-5μ C18 column. The LC/MSeluting system was 1-99% or 10-99% acetonitrile in H₂O with 0.035% v/vtrifluoroacetic acid, 0.035% v/v formic acid, 5 mM HCl or 5 mM ammoniumformate using a 3 or 15 minute linear gradient and a flow rate of 12mL/minute. Silica gel chromatography was performed using silica gel-60with a particle size of 230-400 mesh. Pyridine, dichloromethane(CH₂Cl₂), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile(ACN), methanol (MeOH), and 1,4-dioxane were from Aldrich Sure-Sealbottles kept under dry nitrogen. All reactions were stirred magneticallyunless otherwise noted.

Preparation of10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

To a solution of 2-amino-1-phenyl-ethanol (12.0 g, 87.48 mmol) inmethanol (60 mL) was added benzaldehyde (9.3 g, 8.9 mL, 87.48 mmol) andthe reaction mixture was stirred for 1 hour at room temperature. Thereaction mixture was then cooled to 0° C. and sodium borohydride (3.3 g,87.48 mmol) was added. The reaction mixture was gradually allowed towarm to room temperature and stirred overnight. The reaction mixture wasconcentrated in vacuo, diluted with water, and filtered. The residue wasrinsed with cold isopropanol (3×), then dried in vacuo to give2-(benzylamino)-1-phenylethanol as white crystals (14.0 g, 70%). ESI-MSm/z calc. 227.1. found 228.2 (M+1)⁺; Retention time: 0.8 minutes (3 minrun). ¹H NMR (400 MHz, MeOD) δ 7.37-7.27 (m, 8H), 7.27-7.19 (m, 2H),4.78 (dd, J=8.5, 4.5 Hz, 1H), 3.77 (q, J=13.0 Hz, 2H), 2.82-2.68 (m,2H).

Step 2:

A solution of 2-(benzylamino)-1-phenylethanol (5.3 g, 23.44 mmol) andtert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (5.0 g, 23.44 mmol)in ethanol (30 mL) was heated overnight at 75° C. The solvent wasevaporated and the crude material was used in the next step withoutfurther purification. ESI-MS m/z calc. 440.2. found 441.7 (M+1)⁺;Retention time: 1.41 minutes (3 min run).

Step 3:

To tert-butyl4-[[benzyl-(2-hydroxy-2-phenyl-ethyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(6.2 g, 14.07 mmol) was added HBr (60 mL of 48% w/w,) and the reactionmixture was stirred at 55° C. for 10 hours. The reaction mixture wasevaporated in vacuo, basified the aqueous with 50% aq. NaOH to pH13,then extracted with DCM (3×75 mL). The combined organics were dried overMgSO₄, filtered and concentrated in vacuo to give4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (4.4 g, 97%) as ayellow oil, which was used directly without further purification. ESI-MSm/z calc. 322.2. found 323.7 (M+1)⁺; Retention time: 1.72 minutes (3 minrun).

Step 4:

To crude 4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (4.1 g,12.72 mmol) in DCM (15 mL) was added Boc₂O (2.8 g, 2.9 mL, 12.72 mmol)and the reaction mixture was stirred for 2 hours. The solvent wasremoved in vacuo and the residue was purified by silica gel columnchromatography using 0-60% EtOAc/hexane as eluent to give tert-butyl10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate as awhite foam (3.6 g, 66%). ESI-MS m/z calc. 422.3. found 423.7 (M+1)⁺;Retention time: 1.71 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ7.38-7.25 (m, 10H), 4.88-4.78 (m, 1H), 3.69 (s, 2H), 3.57 (d, J=13.3 Hz,1H), 3.39 (d, J=13.3 Hz, 1H), 3.35-3.26 (m, 1H), 3.18-3.06 (m, 1H),3.00-2.91 (m, 1H), 2.67-2.60 (m, 1H), 2.59-2.49 (m, 1H), 2.05-1.89 (m,2H), 1.64-1.57 (m, 1H), 1.53-1.46 (m, 2H), 1.43 (s, 9H).

Step 5:

To tert-butyl10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate(1.58 g, 3.74 mmol) and Pd(OH)₂ (280 mg, 0.40 mmol) in ethanol (16 mL)was added ammonium formate (1.10 g, 17.39 mmol) and the reaction mixturewas heated to 60° C. for 40 min. The reaction mixture was cooled,filtered, concentrated to 10% of original volume, diluted with ethylacetate and washed with sat. aq. NaHCO₃ (pH 10)/brine. The aqueous wasextracted further with ethyl acetate and the combined organics weredried over Na₂SO₄, filtered and concentrated in vacuo to give tert-butyl8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (1.15 g, 93%)as a white solid. ESI-MS m/z calc. 332.2. found 333.3 (M+1)⁺; Retentiontime: 1.13 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.23 (m,5H), 4.69 (dd, J=10.7, 2.7 Hz, 1H), 3.76 (br. s, 2H), 3.31 (t, J=10.7Hz, 1H), 3.17-3.02 (m, 2H), 2.75 (dd, J=35.5, 12.4 Hz, 2H), 2.63 (dd,J=12.3, 10.8 Hz, 1H), 2.49 (d, J=12.5 Hz, 1H), 1.69-1.57 (m, J=12.6 Hz,1H), 1.57-1.39 (m, 11H).

Step 6:

To tert-butyl 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(0.98 g, 2.93 mmol) and NaHCO₃ (0.99 g, 11.73 mmol) in ethanol at roomtemperature was added 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.82 g, 545 μL, 3.52 mmol) and the reaction mixture was heated at 80°C. for 6 hours. The reaction mixture was cooled, the solid precipitatewas removed by filtration and the solvent was removed in vacuo. Theresidue was taken up in DCM and washed sequentially with 1:1NaOH(1N):NaHCO₃ and then brine. The organics were separated, dried oversodium sulfate and concentrated in vacuo to give tert-butyl10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.15 g, 95%). ESI-MS m/z calc. 414.2. found 415.3 (M+1)⁺; Retentiontime: 2.46 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.26 (m,5H), 4.81 (dd, J=10.5, 2.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 1H), 3.09 (s,1H), 2.98 (m, 3H), 2.74 (dd, J=11.0, 1.5 Hz, 1H), 2.51 (d, J=14.1 Hz,1H), 2.40-2.29 (m, 2H), 1.58 (s, 3H), 1.44 (s, 9H).

Step 7:

To tert-butyl10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(779 mg, 1.86 mmol) in dichloromethane (5 mL) was added2,2,2-trifluoroacetic acid (5 mL, 64.90 mmol) at room temperature. Thereaction mixture was stirred for 40 minutes, then diluted withdichloromethane (75 mL) and the organic solution was washed withsaturated sodium bicarbonate (twice) and then brine. The organic layerwas dried over sodium sulfate, filtered and the solvent was removed invacuo to give10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane asan amber oil (585 mg, 99%). ESI-MS m/z calc. 314.2. found 315.3 (M+1)⁺;Retention time: 1.29 minutes (3 min run). ¹H NMR (400 MHz, CD₃CN) δ7.44-7.25 (m, 5H), 4.82 (dd, J=10.6, 2.8 Hz, 1H), 3.74 (br s, 1H), 3.06(q, J=9.8 Hz, 2H), 3.02-2.91 (m, 2H), 2.88 (dd, J=11.2, 1.5 Hz, 1H),2.85-2.74 (m, 3H), 2.34 (d, J=14.8 Hz, 1H), 2.28 (dt, J=10.9, 5.3 Hz,2H), 1.76-1.64 (m, J=16.0, 8.7, 5.3 Hz, 1H), 1.64-1.52 (m, 2H).

Preparation of4-(2,2-difluoroethyl)-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the procedure as described above, using2-difluoroethyl trifluoromethanesulfonate as the alkylation reagent instep 6.

Preparation of4-(2,2-difluoroethyl)-2-(4-fluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the procedure as described above,starting with 2-amino-1-(4-fluorophenyl)ethanol in step 1 and using2-difluoroethyl trifluoromethanesulfonate as the alkylation reagent instep 6. ESI-MS m/z calc. 314.2. found 315.2 (M+1)⁺; Retention time: 1.08minutes (3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(4-fluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the procedure as described above,starting with 2-amino-1-(2-fluorophenyl)ethanol in step 1 and using2-difluoroethyl trifluoromethanesulfonate as the alkylation reagent instep 6. ESI-MS m/z calc. 314.16058. found 315.3 (M+1)⁺; Retention time:1.32 minutes (3 min run).

Preparation of2-(2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)acetonitrile

This compound was prepared using the procedure as described above, using2-chloroacetonitrile as the alkylation reagent in step 6. ESI-MS m/zcalc. 307.8. found 309.4 (M+1)⁺; Retention time: 0.89 minutes (3 minrun).

Preparation of4-benzyl-2-(4-chlorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the steps 1-4 and 7 in the procedure asdescribed above, starting with 2-amino-1-(4-chlorophenyl)ethanol instep 1. ESI-MS m/z calc. 356.9. found 357.3 (M+1)⁺; Retention time: 1.17minutes (3 min run).

Preparation of 4-benzyl-2-(p-tolyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the steps 1-3 in the procedure asdescribed above, starting with 2-amino-1-(p-tolyl)ethanol in step 1.ESI-MS m/z calc. 336.5. found 337.3 (M+1)⁺; Retention time: 0.65 minutes(3 min run).

Preparation of 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

To a solution of tert-butyl8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (735 mg, 2.21mmol) in methanol (10 mL) was added acetaldehyde (107 mg, 136 μL, 2.43mmol), then sodium cyanoborohydride (195 mg, 1.5 mL, 3.10 mmol) and thereaction mixture was stirred for 2 hours. The reaction mixture wasconcentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 aq.sat. NaHCO₃/25% NaOH (10 mL), and the aqueous layer was extracted withDCM (2×25 mL). The combined organics were dried (MgSO₄), concentrated invacuo and purified by silica gel column chromatography using (0-75%EtOAc/DCM) as eluent to give tert-butyl8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540mg, 68%) as a viscous yellow oil. ESI-MS m/z calc. 360.5. found 361.7(M+1)⁺; Retention time: 1.15 minutes (3 min run).

Step 2:

To tert-butyl8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540mg, 1.50 mmol) in DCM (1.5 mL) was added 2,2,2-trifluoroacetic acid (1mL, 12.98 mmol) and the solution was stirred for 30 minutes. Thereaction mixture was concentrated in vacuo, diluted with DCM (50 mL),washed with 1:1 sat. aq. Na₂CO₃/NaHCO₃ (10 ml) and the aqueous wasextracted further with DCM (2×25 mL). The combined organics were dried(MgSO₄) and evaporated to give8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 100%) as apale yellow solid, which was used without further purification. ESI-MSm/z calc. 260.4. found 261.3 (M+1)⁺; Retention time: 0.3 minutes (3 minrun).

Preparation of 8-isobutyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane

This compound was prepared following the above procedure, using2-methylpropanal in step 1. ESI-MS m/z calc. 288.2. found 289.3 (M+1)⁺;Retention time: 0.79 minutes (3 min run).

Preparation of4-ethyl-2-(4-fluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared following the above procedure, usingtert-butyl2-(4-fluorophenyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate instep 1. ESI-MS m/z calc. 278.2. found 279.3 (M+1)⁺; Retention time: 0.20minutes (3 min run).

Preparation of 4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

A mixture of N-benzyl-2-methyl-prop-2-en-1-amine (0.57 g, 3.52 mmol) andtert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.75 g, 3.52 mmol)in ethanol (4 mL) was heated at 80° C. in a sealed vial for 16 hours.The reaction mixture was cooled and concentrated in vacuo to givetert-butyl4-[[benzyl(2-methylallyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(1.32 g, 100%) as a colorless oil. ESI-MS m/z calc. 374.5. found 375.7(M+1)⁺; Retention time: 1.24 minutes (3 min run).

Step 2:

To a solution of tert-butyl4-[[benzyl(2-methylallyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(1.2 g, 3.20 mmol) in 2-methoxy-2-methyl-propane (11 mL) was added aq.NaHCO₃ (4.3 mL of 1 M, 4.30 mmol) then iodine (0.9 g, 181 μL, 3.52 mmol)and the reaction mixture was rapidly stirred for 16 hours. The reactionmixture was diluted with ethyl acetate (25 mL), quenched with 5 mL 1 MNa₂S₂O₃ aq., shaken vigorously and separated. The organic layer waswashed with 1:1 sat. aq. NaHCO₃/1 M Na₂S₂O₃ aq. (10 mL), dried overMgSO₄ and concentrated in vacuo to give the iodide intermediate as acolorless oil. The oil was dissolved in DMSO (4 mL), and NaBH₄ (0.1 g,3.81 mmol) was added and the reaction mixture was heated at 100° C. for2 hours. A further aliquot of NaBH₄ (0.05 g, 1.32 mmol) was added andthe reaction mixture was heated at 100° C. for 2 hours. After cooling,the reaction was quenched with 5 M aq. HCl (5 mL), stirred for 15minutes, then added 5 M aq. NaOH (5 mL) and 1M aq. Na₂S₂O₃ (5 mL). Thereaction mixture was vigorously stirred for 16 hours, then extractedwith ethyl acetate (3×5 mL), dried over MgSO₄ then purified by silicagel column chromatography using 0-100% EtOAc/hexane as eluent to givetert-butyl2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate(0.5 g, 42%) as a colorless oil. ESI-MS m/z calc. 374.5. found 375.7(M+1)⁺; Retention time: 1.24 minutes (3 min run).

Step 3:

To tert-butyl2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate(560 mg, 1.50 mmol) was added hydrogen chloride (7.5 mL of 4 M indioxane, 29.90 mmol), followed by ethanol (2 mL) and the reactionmixture was stirred for 30 minutes. The reaction mixture wasconcentrated in vacuo, dissolved in water (5 mL), washed with methyltert-butyl ether (5 mL), basified with solid NaHCO₃ then adjusted to pH13-14 with 50% aq. NaOH. The aqueous layer was extracted with ethylacetate (3×25 mL), dried over MgSO₄ and concentrated to give2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane (400 mg, 98%) asa yellow oil, which was used directly without further purification.ESI-MS m/z calc. 274.4. found 275.5 (M+1)⁺; Retention time: 0.75 minutes(3 min run).

Step 4:

To 2-benzyl-4,4-dimethyl-5-oxa-2,9-diazaspiro[5.5]undecane (170 mg, 0.62mmol) and pyridine (98 mg, 100 μL, 1.24 mmol) in DCM (2 mL) at −78° C.was added dropwise trifluoroacetic anhydride (130 mg, 86 μL, 0.62 mmol)and the reaction mixture was allowed to warm to room temperature over 16hours. The reaction mixture was then concentrated in vacuo and purifiedby silica gel column chromatography using 0-100% EtOAc/DCM as eluent togive1-(8-benzyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone(160 mg, 70%) as a colorless oil. ESI-MS m/z calc. 370.4. found 371.1(M+1)⁺; Retention time: 1.48 minutes (3 min run).

Step 5:

A mixture of acetic acid (100 μL, 1.76 mmol), Pd(OH)₂ (11 mg, 0.02mmol),1-(8-benzyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone(80 mg, 0.22 mmol), HCl (108 μL of 4 M in dioxane, 0.43 mmol) andethanol (2 mL) was treated to an atmosphere of hydrogen at 85 psi for 3days. The reaction mixture was filtered and the catalyst was washed withmethanol, then concentrated in vacuo to give1-(10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanoneacetic acid salt as a yellow solid. ESI-MS m/z calc. 280.1. found 281.5(M+1)⁺; Retention time: 0.91 minutes (3 min run).

Step 6:

To1-(10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanoneacetic acid salt (90 mg, 0.26 mmol) in ethanol (1.4 mL) was added NaHCO₃(89 mg, 1.06 mmol) then iodoethane (42 μL, 0.53 mmol). The reactionmixture was heated at 60° C. for 5 hours, then at room temperature for72 hours, then microfiltered and purified by prep LCMS (1-99% ACN/Water,5 mM HCl modifier) to give1-(8-ethyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanonehydrochloride salt (47 mg, 52%) as a white solid. ESI-MS m/z calc.308.2. found 309.7 (M+1)⁺; Retention time: 0.90 minutes (3 min run).

Step 7:

To1-(8-ethyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanonehydrochloride salt (47 mg, 0.14 mmol) and lithium hydroxide (10 mg, 0.42mmol) was added water (0.15 mL) and THF (0.6 mL) and the reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo, partitioned between DCM (10 mL)/1:1brine:NH₄OH (2 mL), extracted with DCM (5×10 mL), dried over MgSO₄ andconcentrated in vacuo to give4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane (24 mg, 81%).ESI-MS m/z calc. 212.2. found 213.5 (M+1)⁺; Retention time: 0.19 minutes(3 min run).

Preparation of9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid

The synthesis of tert-butyl4-[(benzylamino)methyl]-4-hydroxy-piperidine-1-carboxylate was carriedout as described above.

Step 1:

To tetrakis(triphenylphosphine)palladium(0) (487 mg, 0.42 mmol) andtriphenylphosphine (442 mg, 1.69 mmol) in degassed THF (75 mL) was addedtriethylamine (2.35 mL, 16.85 mmol). The reaction mixture was stirredfor 1 hour under an atmosphere of nitrogen. A solution of tert-butyl4-[(benzylamino)methyl]-4-hydroxy-piperidine-1-carboxylate (2.7 g, 8.43mmol) in degassed THF (10 mL) was added via cannula, followed by theaddition of [(Z)-4-acetoxybut-2-enyl]acetate (1.35 mL, 8.47 mmol) andthe reaction mixture was stirred in a sealed pressure flask at 45° C.for 16 hours. The reaction mixture was concentrated in vacuo, dilutedwith ethyl acetate, chilled to −15° C., and the solid was removed byfiltration over Celite®. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography using 0-60%EtOAc/hexane as eluent to give tert-butyl10-benzyl-8-vinyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (2.9g, 92%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.19 (m,5H), 5.77 (ddd, J=17.3, 10.6, 5.5 Hz, 1H), 5.36-5.23 (m, 1H), 5.13 (dt,J=10.6, 1.4 Hz, 1H), 4.25 (s, 1H), 3.64 (s, 2H), 3.53 (d, J=13.3 Hz,1H), 3.37 (d, J=13.3 Hz, 1H), 3.29 (s, 1H), 3.10 (s, 1H), 2.84-2.72 (m,1H), 2.55 (dd, J=11.1, 1.4 Hz, 1H), 2.41 (d, J=13.7 Hz, 1H), 1.95-1.75(m, 2H), 1.50-1.34 (m, 11H).

Step 2:

To tert-butyl10-benzyl-8-vinyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (2.07g, 5.56 mmol) and 4-methylmorpholine 4-oxide (725 mg, 6.19 mmol) inacetone (19 mL) and water (2 mL) was added osmium tetroxide in water(704 μL of 2.5% w/w, 0.06 mmol) dropwise and the solution was stirredfor 2 hours. The reaction mixture was quenched with 1M sodiumthiosulfate (50 mL) and stirred for 5 minutes, then extracted with EtOAc(4×50 mL), washed with sat. aq. NaHCO₃ (30 mL), and dried over MgSO₄,filtered and concentrated in vacuo to give the diol intermediate. Thediol was diluted with DCM (20 mL), filtered over a plug of neutralalumina, washing extensively with 20% MeOH/DCM (>1 L). The filtrate wasconcentrated in vacuo to give tert-butyl8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(2.10 g, 93%) as a white foam. ESI-MS m/z calc. 406.5. found 407.7(M+1)⁺; Retention time: 1.13 (3 min run) ¹H NMR (400 MHz, DMSO) δ7.36-7.27 (m, 4H), 7.27-7.21 (m, 1H), 4.62 (d, J=5.9 Hz, 1H), 4.34 (t,J=5.6 Hz, 1H), 3.74-3.49 (m, 4H), 3.45 (d, J=7.6 Hz, 2H), 3.42-3.33 (m,2H), 3.23 (tt, J=5.7, 2.7 Hz, 1H), 2.94 (d, J=10.6 Hz, 2H), 2.59 (ddd,J=11.7, 8.5, 2.3 Hz, 1H), 2.35 (ddd, J=8.9, 5.2, 1.8 Hz, 1H), 1.81-1.67(m, 2H), 1.38 (s, 9H), 1.34 (dd, J=6.7, 3.0 Hz, 2H), 1.29-1.18 (m, 1H).

Step 3:

To tert-butyl8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.5 g, 3.69 mmol) in THF (35 mL) was added NaIO₄ (2 g, 9.4 mmol)followed by the addition of H₂O (13 mL). The reaction mixture wasstirred at room temp for 2.5 hours. The reaction mixture was filtered,then concentrated in vacuo and the residue was partitioned between sat.aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The aqueouslayer was extracted further with ethyl acetate (2×50 mL). The organiclayers were combined, dried over MgSO₄, filtered and concentrated invacuo. To the intermediate aldehyde (˜1.4 g) was added ^(t)BuOH (17 mL)and 2-methylbut-2-ene (10.5 mL, 99.04 mmol) and the reaction mixture wascooled to 0° C. A solution of NaClO₂ (1.1 g, 9.65 mmol) and NaH₂PO₄(1.33 g, 9.67 mmol) in water (17 mL) was added dropwise over 5 minutes,and the reaction mixture was stirred for 30 minutes at 0° C. Thereaction mixture was warmed to room temperature, then extracted withethyl acetate (4×50 mL) and the combined organics were dried over MgSO₄,filtered and concentrated in vacuo to give the crude acid as a yellowoil. The oil was dissolved in toluene (2.5 mL) and methanol (2.5 mL),then diazomethyl(trimethyl)silane (1.85 mL of 2 M in hexanes, 3.69 mmol)was added dropwise until faint yellow color persisted. Acetic acid wasadded to make solution colorless (2 drops). The reaction mixture wasconcentrated in vacuo then purified by silica gel column chromatographyusing 0-70% EtOAc/hexane as eluent to give 9-tert-butyl 2-methyl4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (1 g, 67%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.20 (m, 5H), 4.43(dd, J=10.5, 2.1 Hz, 1H), 3.74 (s, 3H), 3.57 (d, J=13.3 Hz, 3H),3.45-3.29 (m, 2H), 3.14 (t, J=10.9 Hz, 1H), 3.08-3.01 (m, 1H), 2.56 (dd,J=11.3, 0.9 Hz, 1H), 2.30 (dd, J=8.7, 5.7 Hz, 1H), 2.13 (dd, J=19.9, 8.9Hz, 1H), 1.91 (d, J=11.3 Hz, 1H), 1.69-1.46 (m, 3H), 1.43 (s, 9H).ESI-MS m/z calc. 404.5. found 405.7 (M+1)⁺; Retention time: 1.62 (3 minrun).

Step 4:

A mixture of 9-tert-butyl 2-methyl4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (670 mg,1.66 mmol), ammonium formate (623 mg, 9.936 mmol) and palladium, 10 wt.% on activated carbon (353 mg, 3.31 mmol) in EtOH (5 mL) was heated at65° C. for 50 minutes. The reaction mixture was cooled to roomtemperature, filtered and partitioned between EtOAc/1M aq. NaOH. Thelayers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to yield 9-tert-butyl 2-methyl1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate as a foam (386 mg,74%). ESI-MS m/z calc. 314.2. found 315.5 (M+1)⁺; Retention time: 0.99minutes (3 min run).

Step 5:

2,2,2-Trifluoroethyl trifluoromethanesulfonate (164 μL, 1.06 mmol) wasadded to a solution of 9-tert-butyl 2-methyl1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (222 mg, 0.71 mmol)and NaHCO₃ (237 mg, 2.83 mmol) in anhydrous EtOH (6 mL) at roomtemperature. The reaction mixture was purged with argon, sealed with acap and heated at 70° C. for 12 hours. The reaction mixture was cooledto room temperature, filtered and concentrated in vacuo. The crudematerial was purified by silica gel column chromatography using 0 to 30%EtOAc in DCM as eluent to yield 9-tert-butyl 2-methyl4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate(197 mg, 68%). ESI-MS m/z calc. 410.4. found 411.5 (M+1)⁺; Retentiontime: 2.08 minutes (3 min run).

Step 6:

9-Tert-butyl 2-methyl4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate(197 mg, 0.48 mmol) was dissolved in MeOH (1 mL)/H₂O (1 mL), followed bythe addition of LiOH (46 mg, 1.92 mmol) and the reaction mixture wasstirred for 2 hours at room temperature. The solvent was removed invacuo and the residue was dissolved in water (2 mL) and cooled to 0° C.,then acetic acid (115 mg, 109 μL, 1.92 mmol) was added dropwise (pH=5).The product was partitioned between EtOAc/water, the layers wereseparated and the aqueous layer was extracted once more with EtOAc. Theorganics were dried over Na₂SO₄, filtered and concentrated in vacuo toyield an oil. The oil was co-evaporated twice with toluene and driedunder high vacuum to yield9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid (142 mg, 77%) as a white foam. ESI-MS m/z calc. 382.4. found 383.5(M+1)⁺; Retention time: 1.58 minutes (3 min run).

Preparation of9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid

This compound was prepared using the chemistry as described above using2,2-difluoroethyl trifluoromethanesulfonate as the alkylating agent instep 5. ¹H NMR (400 MHz, DMSO) δ 6.28 (t, J=4.1 Hz, 1H), 6.14 (t, J=4.0Hz, 1H), 6.00 (t, J=4.1 Hz, 1H), 4.20 (d, J=8.8 Hz, 1H), 3.49 (d, J=9.0Hz, 2H), 3.22 (s, 1H), 3.04 (d, J=10.3 Hz, 2H), 2.72 (ddd, J=14.4, 13.7,7.8 Hz, 3H), 2.23-1.94 (m, 3H), 1.58-1.28 (m, 11H); ESI-MS m/z calc.364.4. found 365.3 (M+1)⁺; Retention time: 1.36 minutes (3 min run).

Preparation of9-(tert-butoxycarbonyl)-4-(tert-butyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid

This compound was prepared using steps 1-3 and 6 in the chemistrydescribed above using tert-butyl4-((tert-butylamino)methyl)-4-hydroxypiperidine-1-carboxylate in step 1.¹H NMR (400 MHz, CDCl₃) δ 4.32 (d, J=10.6 Hz, 1H), 4.21-4.16 (m, 1H),3.84-3.50 (m, 3H), 3.33 (t, J=20.1 Hz, 2H), 3.14 (d, J=10.9 Hz, 1H),2.78 (d, J=11.4 Hz, 1H), 2.23 (s, 1H), 2.09 (dt, J=24.2, 13.0 Hz, 4H),1.59 (dd, J=49.3, 11.8 Hz, 3H), 1.42 (d, J=29.3 Hz, 12H), 1.00 (d,J=36.2 Hz, 10H); ESI-MS m/z calc. 356.2. found 357.5 (M+1)⁺; Retentiontime: 0.66 minutes (3 min run).

Preparation of9-(tert-butoxycarbonyl)-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid

This compound was prepared using steps 1-3 and 6 in the chemistrydescribed above using tert-butyl4-((ethylamino)methyl)-4-hydroxypiperidine-1-carboxylate in step 1.ESI-MS m/z calc. 328.5. found 329.5 (M+1)⁺; Retention time: 1.44 minutes(3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(5-ethyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid (418 mg, 1.15 mmol), 1-aminobutan-2-one (156 mg, 1.26 mmol) andpropane phosphonic acid anhydride (T3P) (1.095 g, 1.0 mL of 50% w/w,1.72 mmol) in 2-methyltetrahydrofuran (3.1 mL) was added triethylamine(640 μL, 4.59 mmol) at room temperature. The reaction mixture was thenheated at 40° C. for 5 hours. The reaction mixture was cooled quenchedwith sat. aq. NaHCO₃ and extracted with ethyl acetate. The combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo,then purified by silica gel column chromatography using 0-50% EtOAc inDCM to yield tert-butyl4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(300 mg, 60%). ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.30 (m, 1H), 6.09-5.64(m, 1H), 4.31 (dd, J=11.0, 3.0 Hz, 1H), 4.21-4.05 (m, 2H), 3.77 (ddt,J=10.9, 7.5, 6.3 Hz, 2H), 3.39-3.17 (m, 2H), 3.14-2.95 (m, 1H),2.80-2.63 (m, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.41-2.27 (m, 1H), 2.25-2.11(m, 2H), 1.67-1.51 (m, 3H), 1.46 (s, 9H), 1.13 (t, J=7.4 Hz, 3H). ESI-MSm/z calc. 433.2. found 434.5 (M+1)⁺; Retention time: 1.78 minutes (3 minrun).

Step 2:

To tert-butyl4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(200 mg, 0.46 mmol) in THF (2 mL) was added Burgess' salt (275 mg, 1.15mmol) and the reaction mixture was heated at 75° C. under a nitrogenatmosphere for 2 hours. The reaction mixture was cooled to roomtemperature, and partitioned between EtOAc and saturated aq. NaHCO₃. Thelayers were separated and the aqueous layer was extracted once more withEtOAc. The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo to give an orange oil. The residue was purified bysilica gel column chromatography using 0-20% EtOAc in DCM as eluent toyield tert-butyl4-(2,2-difluoroethyl)-2-(5-ethyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(160 mg, 84%) as a colorless oil. ESI-MS m/z calc. 415.2. found 416.5(M+1)⁺; Retention time: 2.06 minutes (3 min run); ¹H NMR (400 MHz,CDCl₃) δ 6.69 (s, 1H), 6.06-5.68 (m, 1H), 4.89 (dd, J=10.7, 2.5 Hz, 1H),3.85-3.58 (m, 2H), 3.37-3.01 (m, 3H), 2.87-2.59 (m, 6H), 2.45 (d, J=13.6Hz, 1H), 2.30 (d, J=11.3 Hz, 1H), 1.65-1.48 (m, 3H), 1.45 (s, 9H), 1.25(t, J=7.6 Hz, 3H).

Step 3:

To a solution of tert-butyl4-(2,2-difluoroethyl)-2-(5-ethyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(154 mg, 0.37 mmol) in DCM (0.4 mL) was added HCl (464 μL of 4 Msolution in dioxane, 1.85 mmol) and the reaction mixture was stirred atroom temperature for 1 hour. The solvent and excess HCl were removedunder reduced pressure and the residue was triturated with Et₂O to yield4-(2,2-difluoroethyl)-2-(5-ethyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecanehydrochloride salt (138 mg, 96%) as a white solid. ESI-MS m/z calc.315.2. found 316.3 (M+1)⁺; Retention time: 1.07 minutes (3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(5-isopropyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the method described above using1-amino-3-methyl-butan-2-one in step 1. ESI-MS m/z calc. 329.2. found330.3 (M+1)⁺; Retention time: 1.12 minutes (3 min run).

Preparation of2-(5-(tert-butyl)oxazol-2-yl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the method described above using1-amino-3,3-dimethyl-butan-2-one in step 1. ESI-MS m/z calc. 343.20.found 344.1 (M+1)⁺; Retention time: 1.23 minutes (3 min run).

Preparation of8-tert-butyl-10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecane

This compound was prepared using the method described above using9-(tert-butoxycarbonyl)-4-(tert-butyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid and 1-aminopropan-2-one in step 1. ESI-MS m/z calc. 293.4. found294.3 (M+1)⁺; Retention time: 0.39 minutes (3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid (520 mg, 1.43 mmol), prop-2-en-1-amine (118 μL, 1.57 mmol) and T3P(2.12 mL of 50% w/w, 3.59 mmol) in 2-methyltetrahydrofuran (4 mL) wasadded triethylamine (597 μL, 4.28 mmol) at room temperature and thereaction mixture was stirred for 2 hours. The reaction mixture was thenquenched with saturated NaHCO₃ solution (3 mL) and stirred for anadditional 10 minutes, then diluted with EtOAc and the layers wereseparated. The aqueous layer was extracted once more with EtOAc, and thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo to an oil. The residue was purified by silica gel columnchromatography using 0-50% EtOAc in hexanes to yield tert-butyl2-(allylcarbamoyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(480 mg, 83%). ESI-MS m/z calc. 403.2. found 404.5 (M+1)⁺; Retentiontime: 1.78 minutes (3 min run).

Step 2:

To tert-butyl2-(allylcarbamoyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(480 mg, 1.19 mmol) and 4-methylmorpholine 4-oxide (153 mg, 1.31 mmol)in acetone (4.5 mL) and water (480 μL) was added osmium tetroxide inwater (75.63 μL of 4% w/w, 0.01 mmol) dropwise and the solution wasstirred for 2.5 hours at room temperature. The reaction mixture wasquenched with 1M sodium thiosulfate (12 mL) and stirred for 5 minutes,then extracted with EtOAc, washed with sat. aq. NaHCO₃, brine, driedover MgSO₄, filtered and concentrated in vacuo to give tert-butyl4-(2,2-difluoroethyl)-2-((2,3-dihydroxypropyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(520 mg, 99%) which was used without further purification. ESI-MS m/zcalc. 437.2. found 438.5 (M+1)⁺; Retention time: 1.54 minutes (3 minrun).

Step 3:

To tert-butyl4-(2,2-difluoroethyl)-2-((2,3-dihydroxypropyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(422 mg, 0.96 mmol) in THF (10 mL) was added NaIO₄ (522 mg, 2.44 mmol)followed by H₂O (4 mL) the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered andpartitioned between sat. aq. sodium bicarbonate/ethyl acetate. Theaqueous layer was extracted further with ethyl acetate (3×50 mL). Theorganics were combined, washed with sat. aq. sodium bicarbonate (50 mL),dried over MgSO₄, and concentrated in vacuo to yield tert-butyl4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(377 mg, 96%) as a white solid, which was taken onto the next stepwithout purification. ESI-MS m/z calc. 405.2. found 406.5 (M+1)⁺;Retention time: 1.32 minutes (3 min run).

Step 4:

To tert-butyl4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(331 mg, 0.82 mmol) in THF (3 mL) was added Burgess' Salt (486 mg, 2.04mmol). The reaction mixture was heated at 70° C. for 20 minutes under anatmosphere of nitrogen. The reaction mixture was cooled to roomtemperature, partitioned between EtOAc and saturated aq. NaHCO₃, thelayers separated and the aqueous layer was extracted once more withEtOAc. The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo to give an orange oil. The residue was purified bysilica gel column chromatography using 0-30% EtOAc in DCM as eluent toyield tert-butyl4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(121 mg, 38%) as an off white foam. ESI-MS m/z calc. 387.2. found 388.3(M+1)⁺; Retention time: 1.81 minutes (3 min run).

Step 5:

HCl (781 μL of 4 M in dioxane, 3.12 mmol) was added to a solution oftert-butyl4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(121 mg, 0.31 mmol) in DCM (0.7 mL) and the reaction mixture was stirredfor 1 hour at room temperature. The solvent and excess HCl was removedunder reduced pressure and the resulting solid was dissolved in methanol(3 mL) and purified by Waters mass directed LC/MS: (1-99% ACN/H₂O (5 mMHCl)). The desired fractions were combined and concentrated in vacuo toyield4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecanehydrochloride salt (95 mg, 94%) as a white solid. ESI-MS m/z calc.287.1. found 288.3 (M+1)⁺; Retention time: 0.96 minutes (3 min run); ¹HNMR (400 MHz, DMSO) δ 8.15 (d, J=0.8 Hz, 1H), 7.23 (d, J=0.8 Hz, 1H),6.22 (tt, J=55.1, 4.0 Hz, 1H), 4.94 (dd, J=10.8, 2.6 Hz, 1H), 3.19-2.79(m, 8H), 2.65-2.54 (m, 2H), 2.25 (dd, J=11.9, 1.5 Hz, 1H), 1.83-1.70 (m,2H), 1.65 (dd, J=15.1, 3.9 Hz, 1H).

Preparation of10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg,0.37 mmol) and Et₃N (188 mg, 259 μL, 1.86 mmol) in2-methyltetrahydrofuran (706 μL). The reaction mixture was then heatedat 45° C. for 2 hours. The reaction mixture was cooled to roomtemperature and partitioned between EtOAc/saturated aq. NaHCO₃. Thelayers were separated and the aqueous layer was extracted with EtOAc(2×). The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo to a dark foam. The crude product was purified bysilica gel column chromatography using 0-50% EtOAC in DCM as eluent toafford tert-butyl10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. found 438.7(M+1)⁺; Retention time: 1.01 minutes (3 min run).

Step 2:

Tert-butyl10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(80 mg, 0.18 mmol) was dissolved in anhydrous THF (1.5 mL) followed bythe addition of Lawesson's reagent (114 mg, 0.27 mmol) and the reactionmixture was heated at 70° C. for 1 hour under an atmosphere of nitrogen.The reaction mixture was cooled to room temperature and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography using 0-10% EtOAc in DCM as eluent to yieldtert-butyl10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(95 mg, 100%). ESI-MS m/z calc. 435.5. found 436.5 (M+1)⁺; Retentiontime: 1.67 minutes (3 min run); ¹H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H),5.20 (dd, J=9.4, 0.8 Hz, 1H), 3.82-3.76 (m, 2H), 3.43 (d, J=10.1 Hz,1H), 3.31-3.21 (m, 1H), 3.09-2.94 (m, 3H), 2.72 (dd, J=11.4, 0.5 Hz,1H), 2.50 (s, 1H), 2.46 (s, 3H), 2.45-2.38 (m, 2H), 1.79-1.67 (m, 1H),1.65-1.57 (m, 1H), 1.53 (dd, J=11.2, 4.8 Hz, 1H), 1.45 (s, 9H).

Step 3:

Hydrogen chloride (229 μL of 4 M solution in dioxane, 0.9160 mmol) wasadded to tert-butyl10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(95 mg, 0.18 mmol) in anhydrous dichloromethane (1 mL) and the reactionmixture was stirred for 2 hours at room temperature. The excess HCl andsolvent were removed under reduced pressure to yield10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecanehydrochloride salt (74 mg, 99%) as a light yellow solid. ESI-MS m/zcalc. 335.1. found 336.5 (M+1)⁺; Retention time: 0.91 minutes (3 minrun).

Preparation of8-ethyl-10-(5-methylthiazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecane

This compound was prepared using the procedure as described abovestarting from9-(tert-butoxycarbonyl)-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid. ESI-MS m/z calc. 281.4. found 282.5 (M+1)⁺; Retention time: 0.20minutes (3 min run).

Preparation of8-(2,2-difluoroethyl)-10-(4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

To 3-tert-butyl O10-methyl8-(2,2-difluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3,10-dicarboxylate(1.50 g, 3.96 mmol) and powdered (N,O)-dimethylhydroxylaminehydrochloride salt (654 mg, 6.71 mmol) in THF (25 mL) at −78° C. wasadded lithium bis(trimethylsilyl)amine (12.6 mL of 1 M, 12.6 mmol) overa period of 5 minutes. The mixture was stirred at the same temperaturefor 15 minutes, it was then warmed to 0° C. and stirred for anadditional 30 minutes. The reaction mixture was quenched with sat. aq.NH₄Cl (30 mL), extracted with ether (3×50 mL), and the combined organicswere dried over MgSO₄, filtered and concentrated in vacuo. The crudematerial was purified by silica gel column chromatography (0-100% ethylacetate/dichloromethane) to give tert-butyl8-(2,2-difluoroethyl)-10-[methoxy(methyl)carbamoyl]-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.38 g, 85%) as a colorless oil. ESI-MS m/z calc. 407.2. found 408.5(M+1)⁺; Retention time: 1.59 minutes (3 min run). ¹H NMR (400 MHz,CDCl₃) δ 5.93-5.61 (m, 1H), 4.66-4.58 (m, 1H), 3.72 (s, 3H), 3.65-3.46(m, 2H), 3.33-3.22 (m, 1H), 3.14 (s, 3H), 2.83-2.77 (m, 1H), 2.70-2.57(m, 3H), 2.47-2.40 (m, 1H), 2.28-2.12 (m, 2H), 1.61-1.48 (m, 3H),1.46-1.35 (m, 10H).

Step 2:

To tert-butyl8-(2,2-difluoroethyl)-10-[methoxy(methyl)carbamoyl]-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(295 mg, 0.72 mmol) in THF (3 mL) at −78° C. under an atmosphere ofnitrogen, was added ethylmagnesium bromide (1.7 mL of 1 M in THF, 1.7mmol) dropwise. The reaction mixture was stirred at the same temperaturefor 0.5 hours, then at 0° C. for 1 hour. The reaction mixture wasquenched with ethyl acetate (20 mL) and sat. aq. NaHCO₃ (10 mL). Theaqueous layer was further extracted with EtOAc (2×20 mL), and thecombined organics were dried over MgSO₄, filtered and concentrated invacuo. The crude material was purified by silica gel columnchromatography (0-100% ethyl acetate/hexane) to give tert-butyl8-(2,2-difluoroethyl)-10-propanoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(227 mg, 83%) as a colorless oil. ESI-MS m/z calc. 376.2. found 377.3(M+1)⁺; Retention time: 1.76 minutes. ¹H NMR (400 MHz, CDCl₃) δ6.01-5.70 (m, 1H), 4.21-4.15 (m, 1H), 3.91-3.75 (m, 2H), 3.33-3.22 (m,1H), 3.15-2.98 (m, 2H), 2.79-2.57 (m, 5H), 2.43-2.35 (m, 1H), 2.19-2.06(m, 2H), 1.61-1.39 (m, 12H), 1.06 (t, J=7.3 Hz, 3H).

Step 3:

tert-Butyl8-(2,2-difluoroethyl)-10-propanoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(225 mg, 0.598 mmol) and DMF-DMA (1.0 mL, 7.53 mmol) were heated in asealed vial at 105° C. overnight. The reaction mixture was concentratedand then diluted with methanol (1 mL). Hydrazine (60 μL, 1.9 mmol) wasadded in 3 aliquots every hour over 3 hours and then the reactionmixture was stirred for an additional 1 hour. The reaction mixture wasdiluted with methanol, microfiltered and purified by preparative LCMS(10-99% ACN/Water, HCl modifier) to give tert-butyl8-(2,2-difluoroethyl)-10-(4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(80 mg, 0.2 mmol, 33.42%) as a yellow oil. ESI-MS m/z calc. 400.2. found401.5 (M+1)⁺; Retention time: 1.36 minutes (3 min run).

Step 4:

To tert-butyl8-(2,2-difluoroethyl)-10-(4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(80 mg, 0.20 mmol) in ethanol (0.2 mL) was added HCl (500 μL of 4 M indioxane, 2.00 mmol) and the reaction mixture was stirred for 1 hour. Thereaction mixture was concentrated in vacuo to give,8-(2,2-difluoroethyl)-10-(4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecanehydrochloride salt as a yellow solid. ESI-MS m/z calc. 300.2. found301.3 (M+1)⁺; Retention time: 0.48 minutes (3 min run). ¹H NMR (400 MHz,DMSO) δ 8.74 (s, 2H), 7.45 (s, 1H), 6.49-6.08 (m, 1H), 5.76 (s, 1H),4.88 (d, J=9.6 Hz, 1H), 3.21-2.57 (m, 10H), 2.06 (s, 3H), 1.81-1.56 (m,4H).

Preparation of8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

To tert-butyl 4-[(benzylamino)methyl]-4-hydroxy-piperidine-1-carboxylate(3.0 g, 9.36 mmol) in DMF (19 mL) at 0° C. was added diisopropylethylamine (3.4 mL, 19.66 mmol) followed by the addition of2-bromo-1-(2-pyridyl)ethanone hydrobromide salt (2.6 g, 9.36 mmol) andreaction mixture was stirred for 2 hours warming from 0° C. to 10° C.The reaction mixture was diluted with ethyl acetate and washed with sat.NaHCO₃ solution and then brine. The organics were separated, dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue, which waspurified using silica gel column chromatography using MeOH/DCM (1-15%)as eluent to give tert-butyl4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate(3.8, 92%). ESI-MS m/z calc. 439.2. found 440.0 (M+1)⁺; Retention time:1.12 minutes (3 min run).

Step 2:

To tert-butyl4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate(190 mg, 0.43 mmol) in benzene (11 mL) was added 4-methylbenzenesulfonicacid (99 mg, 0.52 mmol) and reaction mixture was heated at 80° C. for 30minutes. The reaction mixture was cooled, diluted with ethyl acetate andwashed sequentially with sat. NaHCO₃ and brine solution. The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated invacuo to give residue, which was purified using silica gel columnchromatography using EtOAc/DCM (10-100%) as eluent to give tert-butyl8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate(86 mg, 45%). ESI-MS m/z calc. 421.5. found 422.2 (M+1)⁺; Retentiontime: 1.42 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.40-8.34 (m,1H), 7.56 (dd, J=4.0, 3.5 Hz, 1H), 7.37-7.27 (m, 6H), 7.07 (s, 1H), 6.92(d, J=1.5 Hz, 1H), 4.22 (s, 2H), 3.99-3.76 (m, 2H), 3.17 (t, J=11.8 Hz,2H), 2.78 (s, 2H), 1.83 (s, 2H), 1.44 (s, 9H), 1.40 (d, J=4.4 Hz, 2H).

Step 3:

To tert-butyl8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate(80 mg, 0.19 mmol) in methanol (13 mL) was added Pd(OH)₂ (50 mg, 0.36mmol) and ammonium formate (180 mg, 2.85 mmol) and the reaction mixturewas heated at 70° C. for 1 hour. The reaction mixture was cooled,diluted with ethyl acetate and filtered through Celite®. The organiclayer was washed with 1:1 NaOH:NaHCO₃ solution, dried over Na₂SO₄,filtered and concentrated in vacuo to yield tert-butyl10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg,100%) as an oil which was used in the next step without furtherpurification. ESI-MS m/z calc. 333.4. found 334.4 (M+1)⁺; Retentiontime: 1.00 minutes (3 min run).

Step 4:

To tert-butyl10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg,0.19 mmol) in ethanol was added sodium hydrogen carbonate (64 mg, 0.76mmol) followed by the addition of 2,2-difluoroethyltrifluoromethanesulfonate (49 mg, 0.23 mmol) and reaction mixture washeated at 80° C. for 40 minutes. The reaction mixture was cooled to roomtemperature and diluted with DCM and the organic layer was washed with1:1 NaOH:NaHCO₃ solution. The organics were separated, dried overNa₂SO₄, filtered and concentrated in vacuo to give tert-butyl8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateas an oil. To the oil was added HCl (237.5 μL of 4 M in dioxane, 0.95mmol) at room temperature under an atmosphere of nitrogen and thereaction mixture was stirred for 30 minutes. The solvent was removed invacuo and the residue was triturated with ether to give8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane(45 mg, 79%). ESI-MS m/z calc. 297.3. found 298.4 (M+1)⁺; Retentiontime: 0.35 minutes (3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(6-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the chemistry as described above using2-bromo-1-(6-methyl-2-pyridyl)ethanone in step 1. ESI-MS m/z calc.311.2. found 312.1 (M+1)⁺; Retention time: 0.3 minutes (3 min run).

Preparation of4-(2,2-difluoroethyl)-2-(3-methylpyridin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the chemistry as described above using2-bromo-1-(3-methylpyridin-2-yl)ethanone in step 1. ESI-MS m/z calc.311.4. found 312.0 (M+1)⁺; Retention time: 0.23 minutes (3 min run).

Preparation of8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

To a mixture of3-tert-butoxycarbonyl-8-(2,2-difluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylicacid (100 mg, 0.27 mmol), N,O-dimethylhydroxylamine hydrochloride salt(29 mg, 0.30 mmol) and T3P (245 μL of 50% w/w, 0.41 mmol) in2-methyltetrahydrofuran (1 mL) was added triethylamine (153 μL, 1.10mmol). The reaction mixture was stirred overnight, then diluted withethyl acetate (5 mL), washed with sat. aq. NaHCO₃ (5 mL), dried overMgSO₄ and concentrated in vacuo to give the Weinreb amide intermediate.The intermediate was dissolved in THF (1 mL) and cooled to 0° C. underan atmosphere of nitrogen, and chloro(ethynyl)magnesium (1 mL of 0.6 Min THF, 0.60 mmol) was added dropwise. The reaction mixture was stirredat 0° C. for 2 h, then at room temperature for 1 hour. The reactionmixture was quenched with sat. aq. NH₄Cl, extracted with ethyl acetate,dried over MgSO₄ and purified by silica gel column chromatography using0-100% EtOAc/hexanes eluent to give tert-butyl8-(2,2-difluoroethyl)-10-prop-2-ynoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(25 mg, 24%) as a colorless oil. ESI-MS m/z calc. 372.4. found 373.1(M+1)⁺; Retention time: 1.82 (3 min run; ¹H NMR (400 MHz, CDCl₃) δ 5.84(tt, J=55.8, 4.2 Hz, 1H), 4.30 (d, J=8.6 Hz, 1H), 3.78 (s, 2H), 3.38 (s,1H), 3.34 (d, J=10.2 Hz, 1H), 3.13 (dd, J=30.8, 11.3 Hz, 2H), 2.86-2.56(m, 3H), 2.35 (d, J=14.6 Hz, 1H), 2.22 (dd, J=22.1, 11.2 Hz, 2H),1.70-1.36 (m, 12H).

Step 2:

A solution of tert-butyl8-(2,2-difluoroethyl)-10-prop-2-ynoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(25 mg, 0.07 mmol), hydrazine (42 μL, 1.34 mmol) and ethanol (0.5 mL)was stirred for 1 hour at room temperature. The solution wasconcentrated in vacuo to give the crude pyrazole as a yellow oil. HCl(400 μL of 4 M in dioxane, 1.60 mmol) followed by ethanol (0.2 mL) wasadded and the reaction mixture was stirred for 15 minutes at roomtemperature. The reaction mixture was concentrated in vacuo to give8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecaneas a gummy yellow solid. ESI-MS m/z calc. 286.2. found 287.1 (M+1)⁺;Retention time: 0.32 minutes (3 min run).

Preparation of2-(1H-pyrazol-3-yl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the chemistry as described abovestarting from9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid. ESI-MS m/z calc. 304.2. found 305.3 (M+1)⁺; Retention time: 0.76minutes (3 min run).

Preparation of2-(5-methyl-1H-pyrazol-3-yl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

This compound was prepared using the chemistry as described abovestarting from9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylicacid and using bromo-prop-1-ynyl-magnesium. ESI-MS m/z calc. 318.2.found 319.1 (M+1)⁺; Retention time: 0.85 minutes. (3 min run).

Preparation of 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane

Step 1:

A solution of tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7g, 3.42 mmol) and 2-[(4-methoxyphenyl)methylamino]-2-phenyl-ethanol (800mg, 3.109 mmol) in ethanol (5 mL) was stirred at 60° C. for 72 hours.The reaction mixture was concentrated in vacuo and purified by silicagel column chromatography using 0 to 10% MeOH in DCM as eluent to yieldtert-butyl4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate(1.2 g, 82%). ESI-MS m/z calc. 470.6. found 471.5 (M+1)⁺; Retentiontime: 1.45 minutes (3 min run).

Step 2:

To a solution of tert-butyl4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate(1.0 g, 2.13 mmol) in THF (10 mL) was added DIEA (1.1 mL, 6.38 mmol)followed by an addition of a solution of methylsulfonyl methanesulfonate(1.1 g, 6.38 mmol) in THF (2 mL) under an atmosphere of nitrogen at 0°C. The reaction mixture was warmed to room temperature and then heatedat 40° C. for 16 hours. The reaction mixture was quenched with water andthe aqueous layer was extracted with DCM. The organic layer was washedwith a sat. solution of NaHCO₃, followed by washing with water. Theorganic layer was dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using 0 to 100%DCM in hexanes as eluent to obtain tert-butyl8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(0.5 g, 51%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)⁺; Retentiontime: 1.62 minutes (3 min run).

Step 3:

To tert-butyl8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(500 mg, 1.11 mmol), Pd (500 mg, 4.70 mmol) and ammonium formate (697mg, 11.05 mmol) was added methanol. The reaction mixture was then heatedat 70° C. for 16 hours. The reaction mixture was filtered through a plugof celite and the solvent was concentrated in vacuo to obtain tert-butyl9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (340 mg, 93%)as an oil. ESI-MS m/z calc. 332.4. found 333.5 (M+1)⁺; Retention time:1.21 minutes (3 min run).

Step 4:

To a solution of tert-butyl9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (336 mg, 1.01mmol) in ethanol (3 mL) was added acetaldehyde (62 μL, 1.11 mmol) thensodium cyanoborohydride (89 mg, 1.42 mmol) and the reaction mixture wasstirred for 2 hours. The reaction mixture was concentrated in vacuo,partitioned between DCM (50 mL) and 1:1 aq. sat. NaHCO₃/25% NaOH (10mL), and the aqueous layer was further extracted with DCM (2×25 mL). Thecombined organics were dried with MgSO₄ and concentrated in vacuo togive tert-butyl8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (298mg, 82%). ESI-MS m/z calc. 360.5. found 361.7 (M+1)⁺; Retention time:1.30 minutes (3 min run).

Step 5:

To a solution of tert-butyl8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (295mg, 0.82 mmol) in DCM (3 mL) was added hydrogen chloride (2 mL of 4 Mdioxane, 8.18 mmol). The reaction mixture was stirred for 1 hour. Thesolvent was decanted and the residue was triturated with methanol andhexanes. The solvent was concentrated in vacuo to obtain8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride salt(230 mg, 95%) as a fluffy solid. ESI-MS m/z calc. 260.2. found 261.1(M+1)⁺; Retention time: 0.2 minutes (3 min run).

Preparation of tert-butyl9-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate

This compound was prepared using the chemistry as described abovestarting from tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.ESI-MS m/z calc. 212.2. found 213.5 (M+1)⁺; Retention time: 0.21 minutes(3 min run).

Preparation of2-(methoxymethyl)-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

A mixture of tert-butyl8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(4.10 g, 10.9 mmol), ammonium formate (6.87 g, 109 mmol) and Pd(OH)₂(1.53 g, 10.9 mmol) was heated at 60° C. for 1 h. The reaction mixturewas cooled, filtered, and concentrated in vacuo to provide tert-butyl10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(3.10 g, 10.8 mmol, 99%). ESI-MS m/z calc. 286.2. found 287.2 (M+1)⁺;Retention time: 0.75 minutes (3 min run).

Step 2:

A solution of tert-butyl10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(3.10 g, 10.8 mmol), 2-chloropyrimidine (1.86 g, 16.2 mmol) and sodiumcarbonate (2.30 g, 21.7 mmol) in DMSO (15 mL) was heated at 110° C. for1 h. The reaction mixture was diluted with ethyl acetate (200 mL),washed with water (4×100 mL), dried over Na₂SO₄, and concentrated invacuo. Silica gel column chromatography (0-60% ethyl acetate/hexane)provided tert-butyl10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(3.18 g, 8.73 mmol, 80%). ESI-MS m/z calc. 364.2. found 365.3 (M+1)⁺;Retention time: 1.21 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.29(d, J=4.7 Hz, 2H), 6.50 (t, J=4.7 Hz, 1H), 4.64 (ddd, J=16.0, 8.5, 1.5Hz, 2H), 3.90-3.80 (m, 1H), 3.79-3.56 (m, 4H), 3.44-3.22 (m, 1H), 3.13(t, J=10.6 Hz, 1H), 2.90-2.71 (m, 2H), 2.19 (d, J=8.9 Hz, 1H), 1.98 (dd,J=10.6, 3.6 Hz, 1H), 1.69-1.58 (m, 2H), 1.45 (s, 9H).

Step 3:

To a solution of tert-butyl10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.45 g, 3.98 mmol) in dichloromethane (15 mL) was added triethylamine(1.66 mL, 11.9 mmol) and 4-(dimethylamino)-pyridine (195 mg, 1.59 mmol)at 0° C. Tosyl chloride (910 mg, 4.78 mmol) was then added in oneportion. The reaction mixture was allowed to warm to room temperatureand stirred for 16 h. The reaction mixture was quenched with water andthe layers were separated. The aqueous layer was extracted withdichloromethane, and the combined organic layers washed with saturatedsodium bicarbonate solution and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel columnchromatography (0-80% ethyl acetate/hexanes) provided tert-butyl4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(1.83 g, 3.53 mmol, 89%). ESI-MS m/z calc. 518.2. found 519.3 (M+1)⁺;Retention time: 1.83 minutes (3 min run). ¹H NMR (400 MHz, MeOD) δ 8.31(d, J=4.8 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.60(t, J=4.8 Hz, 1H), 4.67-4.48 (m, 2H), 4.12 (d, J=4.6 Hz, 2H), 3.89 (ddd,J=12.0, 7.5, 4.6 Hz, 1H), 3.71-3.56 (m, 2H), 3.05 (ddd, J=20.6, 17.0,8.8 Hz, 2H), 2.80-2.65 (m, 2H), 2.46 (s, 3H), 1.88 (d, J=14.1 Hz, 1H),1.50 (dt, J=7.9, 4.0 Hz, 2H), 1.45 (s, 9H), 1.38-1.27 (m, 1H).

Step 4:

Tert-butyl4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(1.83 g, 3.53 mmol) was dissolved in a solution of sodium methoxide (71mL of 0.5 M in methanol, 35 mmol) and refluxed for 18 h. The solvent wasevaporated to dryness and the residue dissolved in dichloromethane (200mL). The solution was washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. Silica gel chromatography (5-80%ethyl acetate/hexanes) provided tert-butyl10-(methoxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateas colorless oil. ESI-MS m/z calc. 378.2. found 379.3 (M+1)⁺; Retentiontime: 1.54 minutes (3 min run). ¹H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8Hz, 2H), 6.58 (t, J=4.8 Hz, 1H), 4.72-4.52 (m, 2H), 3.91 (ddd, J=10.9,7.9, 4.9 Hz, 1H), 3.76-3.59 (m, 2H), 3.56-3.44 (m, 2H), 3.40 (s, 3H),3.13 (t, J=11.1 Hz, 1H), 2.85-2.65 (m, 2H), 1.98 (d, J=14.6 Hz, 2H),1.59 (dd, J=8.7, 4.5 Hz, 2H), 1.45 (s, 9H), 1.44-1.37 (m, 1H).

Step 5:

Tert-butyl10-(methoxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.18 g, 3.12 mmol) was dissolved in dichloromethane (2 mL) and treatedwith a solution of HCl (1.6 mL of 4 M in dioxane, 6.2 mmol). The mixturewas allowed to stir for 2 h. The reaction mixture was evaporated todryness to provide2-(methoxymethyl)-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecanehydrochloride. ESI-MS m/z calc. 278.2. found 279.2 M+1)⁺; Retentiontime: 0.68 min (3 min run). ¹H NMR (400 MHz, MeOD) δ 8.59 (d, J=5.2 Hz,2H), 6.99 (t, J=5.2 Hz, 1H), 4.52 (ddd, J=44.3, 13.4, 1.7 Hz, 2H),4.12-3.97 (m, 1H), 3.56 (ddd, J=26.1, 10.3, 4.9 Hz, 2H), 3.42 (s, 3H),3.34 (dd, J=10.9, 5.0 Hz, 2H), 3.27-3.19 (m, 2H), 3.13 (dd, J=13.2, 11.1Hz, 2H), 2.42 (d, J=15.2 Hz, 1H), 1.94 (dd, J=10.7, 4.3 Hz, 2H), 1.74(ddd, J=15.3, 12.8, 4.4 Hz, 1H).

Preparation of2-ethyl-4-(pyridin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To a solution of tert-butyl10-benzyl-8-vinyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (3.10g, 8.32 mmol) in methanol (60 mL) was added Pd(OH)₂ (1.40 g, 9.99 mmol)and ammonium formate (10.5 g, 166 mmol) and the mixture heated at 55° C.for 20 min. The reaction mixture was filtered, concentrated to ˜10 mL,then diluted with dichloromethane and saturated sodium bicarbonatesolution. The organic layer was separated and the aqueous layerextracted with dichloromethane (5×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated in vacuo to providetert-butyl 4-ethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (2.27g, 7.99 mmol, 96%). ESI-MS m/z calc. 284.21. found 285.1 (M+1)⁺;Retention time: 1.09 minutes (3 min run).

Step 2:

A solution of rac-BINAP (43.8 mg, 0.070 mmol) and Pd₂(dba)₃ (32.2 mg,0.0352 mmol) in toluene (1 mL) was stirred under nitrogen atmosphere ina sealed vial at 90° C. for 10 min, then cooled to 40° C. and cannulatedinto a stirring solution of tert-butyl4-ethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 1.76mmol) and 2-chloropyridine (200 mg, 165 μL, 1.76 mmol) in toluene (6mL). The solution was treated with sodium tert-butoxide (275 mg, 2.87mmol), flushed with nitrogen and stirred for 3 h at 90° C. The reactionmixture was cooled, diluted with ethyl acetate (100 mL), filteredthrough Celite and concentrated in vacuo. Silica gel chromatography (120g silica, 10-70% ethyl acetate/hexane) provided tert-butyl10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(486 mg, 1.34 mmol, 76%) as an orange-colored oil. ESI-MS m/z calc.361.2. found 362.3 (M+1)⁺; Retention time: 1.25 minutes (3 min run). ¹HNMR (400 MHz, DMSO-d₆) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.51 (ddd, J=8.8,7.1, 2.0 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.61 (dd, J=6.7, 4.9 Hz, 1H),4.24 (d, J=12.0 Hz, 1H), 4.11 (d, J=12.9 Hz, 1H), 3.75-3.51 (m, 3H),3.15 (br s, 1H), 2.91 (br s, 1H), 2.59 (d, J=13.0 Hz, 1H), 2.40 (dd,J=12.6, 10.9 Hz, 1H), 2.02 (d, J=13.3 Hz, 1H), 1.60-1.42 (m, 4H), 1.39(s, 9H), 1.36-1.26 (m, 1H), 0.95 (t, J=7.5 Hz, 3H).

Step 3:

Tert-butyl10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(480 mg, 1.33 mmol) was dissolved in dichloromethane (5 mL) at 0° C. andtreated dropwise with HCl in dioxane (2.65 mL of 4 M, 10.6 mmol). Thereaction was then allowed to warm to room temperature and stirred for 1h. The reaction mixture was diluted with dichloromethane (50 mL) andsaturated sodium bicarbonate solution. The organic layer was separatedand the aqueous layer extracted with dichloromethane (3×20 mL). Theaqueous layer was further diluted with 25 mL of 1 N NaOH and extractedwith dichloromethane (3×20 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated to provide10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (345 mg, 1.32mmol, 99%) an orange-colored oil. ESI-MS m/z calc. 261.2. found 262.3(M+1)⁺; Retention time: 0.3 minutes (3 min run). ¹H NMR (400 MHz,DMSO-d₆) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.50 (ddd, J=8.8, 7.1, 2.0 Hz,1H), 6.84 (d, J=8.6 Hz, 1H), 6.60 (dd, J=6.6, 5.0 Hz, 1H), 4.17 (t,J=11.3 Hz, 2H), 3.58-3.54 (m, 2H), 2.96-2.84 (m, 1H), 2.81-2.71 (m, 1H),2.71-2.65 (m, 2H), 2.55 (d, J=12.9 Hz, 1H), 2.40 (dd, J=12.6, 11.0 Hz,1H), 1.93 (d, J=13.9 Hz, 1H), 1.59-1.38 (m, 5H), 0.96 (t, J=7.5 Hz, 3H).

Preparation of4-(but-2-ynyl)-2-(fluoromethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To a solution of tert-butyl8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(2.00 g, 5.31 mmol) in methanol (38 mL) was added Pd(OH)₂ (671 mg, 4.78mmol) and ammonium formate (4.02 g, 63.7 mmol) and the mixture heated at50° C. for 1 h. Additional catalyst (2.6 mmol) and ammonium formate (25mmol) were added and the reaction heated for an additional 2 h. Thereaction mixture was filtered and concentrated to ˜10 mL volume. Theconcentrate was diluted with dichloromethane and saturated sodiumbicarbonate solution. The organic layer was separated and the aqueouslayer washed with dichloromethane (5×50 mL). The combined organics weredried over Na₂SO₄, filtered, and concentrated to provide tert-butyl10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.37 g, 4.77 mmol, 90%) a s an amber-colored glass. ESI-MS m/z calc.286.2. found 287.3 (M+1)⁺; Retention time: 0.65 minutes (3 min run).

Step 2:

Tert-butyl10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.35 g, 4.71 mmol), K₂CO₃ (3.26 g, 23.6 mmol) and 1-bromobut-2-yne (495μL, 5.66 mmol) were combined in N,N-dimethylformamide (15 mL) and heatedfor 48 h at 45° C. under nitrogen. The reaction mixture was diluted withethyl acetate (150 mL) and filtered. The filtrate was washed with water,50% saturated sodium bicarbonate solution, and brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. The desiredfractions obtained from silica gel chromatography (5-20%methanol/dichloromethane) were combined and concentrated, then broughtup in ethyl acetate, filtered and concentrated in vacuo to providetert-butyl-8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.12 g, 3.31 mmol, 70%). ESI-MS m/z calc. 338.2. found 339.3 (M+1)⁺;Retention time: 0.86 minutes (3 min run).

Step 3:

To a solution of diethylaminosulfur trifluoride (19.5 μL, 0.148 mmol) indichloromethane (1.0 mL) at −78° C. was added dropwise a solution oftert-butyl8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(50.0 mg, 0.148 mmol) in dichloromethane (1 mL). The reaction wasstirred for 10 min at −78° C. then allowed to warm to room temperatureand stirred for 16 h. Silica gel chromatography (4 g silica, 0-15%methanol/dichloromethane) provided tert-butyl8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(23.0 mg, 46%). ESI-MS m/z calc. 340.2. found 341.3 (M+1)⁺; Retentiontime: 1.16 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 4.52-4.40 (m,1H), 4.39-4.28 (m, 1H), 4.06-3.91 (m, 1H), 3.71 (br s, 2H), 3.35-3.14(m, 3H), 3.08 (t, J=11.4 Hz, 1H), 2.78 (d, J=10.3 Hz, 1H), 2.58 (d,J=11.1 Hz, 1H), 2.31 (d, J=13.5 Hz, 1H), 2.06 (t, J=12.5 Hz, 2H), 1.84(t, J=2.3 Hz, 3H), 1.57-1.44 (m, 12H).

Step 4:

Tert-butyl8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(23.0 mg, 0.0676 mmol) was dissolved in dichloromethane (2 mL) andtreated with HCl in dioxane (1.69 mL of 4 M, 6.76 mmol). The reactionmixture was stirred for 2 h, then diluted with dichloromethane (10 mL)and 1:1 saturated sodium bicarbonate/1 M NaOH (10 mL). The organic layerwas separated, dried over Na₂SO₄, and concentrated to yield8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecanehydrochloride (16.0 mg, 0.0666 mmol, 98%). ESI-MS m/z calc. 240.2. found241.5 (M+1)⁺; Retention time: 0.22 minutes (3 min run).

Preparation of4-(but-2-ynyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To a solution of tert-butyl4-(aminomethyl)-4-hydroxy-piperidine-1-carboxylate (3.00 g, 13.0 mmol)in N,N-dimethylformamide (30 mL) was added ethyl2-bromo-2,2-difluoro-acetate (2.65 g, 13.0 mmol) and the reactionmixture stirred for 1 h under nitrogen. The reaction mixture was mixturediluted with ethyl acetate and water (25 mL) and brine (25 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated toprovide tert-butyl4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(4.98 g, 12.9 mmol, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (t, J=5.9 Hz,1H), 4.66 (s, 1H), 3.65 (d, J=12.7 Hz, 2H), 3.16 (d, J=6.1 Hz, 2H), 3.02(s, 2H), 1.38 (m, 13H).

Step 2:

To a stirring solution of potassium tert-butoxide (7.23 mL of 1 M, 7.23mmol) in tetrahydrofuran (20 mL) at 70° C. was added a solution oftert-butyl4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(1.4 g, 3.62 mmol) in tetrahydrofuran (20 mL) over 15 min. After 20 minthe reaction mixture was diluted with 1:1 brine/saturated NH₄Cl andethyl acetate. The organic layer was separated, washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (40 g silica, 30-100% ethyl acetate/hexane, productvisualized by TLC with ninhydrin staining+heat) provided tert-butyl4,4-difluoro-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg,1.11 mmol, 31%) as a white solid. ESI-MS m/z calc. 306.1. found 307.5(M+1)⁺; Retention time: 1.32 minutes (3 min run). ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (s, 1H), 3.75 (d, J=13.3 Hz, 2H), 3.45 (d, J=3.2 Hz,2H), 3.07 (br s, 2H), 1.79 (d, J=13.6 Hz, 2H), 1.72-1.60 (m, 2H), 1.41(s, 9H).

Step 3:

Borane dimethylsulfide (36.3 μL, 0.408 mmol) was added dropwise to asolution of tert-butyl10,10-difluoro-9-oxo-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(125 mg, 0.408 mmol) in tetrahydrofuran (3 mL). The reaction mixture washeated at 55° C. for 2 h then cooled to room temperature. The mixturewas quenched with the careful dropwise addition of methanol (˜2 mL).N,N-dimethylethane-1,2-diamine (33.3 μL, 0.313 mmol) was then added andthe mixture heated at 70° C. for 40 min. The reaction was concentrated,and silica gel chromatography (4 g silica, 1% triethylamine/4%methanol/dichloromethane)) provided tert-butyl8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylatewhich was taken directly to the next reaction.

Step 4:

To a mixture of crude tert-butyl10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (65.0mg, 0.222 mmol) and K₂CO₃ (61.5 mg, 0.445 mmol) in N,N-dimethylformamide(1.0 mL) was added 1-bromobut-2-yne (29.2 μL, 0.334 mmol) and thereaction heated at 45° C. for 48 h. The reaction was diluted with ethylacetate and filtered. The filtrate was dried over Na₂SO₄, filtered andconcentrated. Silica gel chromatography (4 g silica, 1-100% ethylacetate/hexane) provided tert-butyl8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(50.0 mg, 65%) as a colorless oil. ESI-MS m/z calc. 344.2. found 345.3(M+1)⁺; Retention time: 1.91 minutes (3 min run). ¹H NMR (400 MHz,CDCl₃) δ 3.80 (br s, 2H), 3.35 (q, J=2.2 Hz, 2H), 3.23 (t, J=12.1 Hz,2H), 2.80 (t, J=8.5 Hz, 2H), 2.48 (s, 2H), 2.02 (d, J=13.2 Hz, 2H), 1.84(t, J=2.3 Hz, 3H), 1.54-1.48 (m, 2H), 1.46 (s, 9H).

Step 5:

Tert-butyl8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(50.0 mg, 0.145 mmol) was dissolved in dichloromethane (1 mL) andtreated with HCl in dioxane (1.3 mL of 4 M, 5.1 mmol). The reactionmixture was stirred for 1 h then concentrated in vacuo several timeswith acetonitrile to yield a white solid. The solid was dissolved in 1:1DCM/acetonitrile and stirred with solid K₂CO₃ for 1 h. The mixture wasfiltered and concentrated to provide8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane (34 mg,96%). ESI-MS m/z calc. 244.1. found 245.3 (M+1)⁺; Retention time: 0.79minutes (3 min run).

Preparation of 4-tert-butyl-2-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To tetrakis(triphenylphosphine)palladium (0) (1.03 g, 0.891 mmol) andtriphenylphosphine (934 mg, 3.56 mmol) in degassed tetrahydrofuran (150mL) in a pressure flask was added triethylamine (5.0 mL, 36 mmol). Themixture was stirred for 1 h under nitrogen atmosphere. A solution oftert-butyl4-[(tert-butylamino)methyl]-4-hydroxy-piperidine-1-carboxylate (5.10 g,17.8 mmol) in degassed tetrahydrofuran (20 mL) was added via cannula,followed by [(Z)-4-acetoxybut-2-enyl]acetate (2.85 mL, 17.9 mmol) andthe mixture was stirred at 45° C. for 16 h. Silica gel chromatography(0-40% ethyl acetate/hexane, ninhydrin stain on TLC to visualize)provided tert-butyl4-tert-butyl-2-vinyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(5.1 g, 15 mmol, 85%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) d5.97-5.65 (m, 1H), 5.29 (dt, J=17.3, 1.6 Hz, 1H), 5.17-5.07 (m, 1H),4.13 (s, 1H), 3.64 (s, 2H), 3.32 (t, J=10.3 Hz, 1H), 3.12 (t, J=11.1 Hz,1H), 2.85 (dt, J=11.0, 2.5 Hz, 1H), 2.68 (dd, J=11.1, 2.2 Hz, 1H), 2.33(d, J=14.2 Hz, 1H), 2.00-1.73 (m, 2H), 1.66-1.49 (m, 3H), 1.51-1.35 (m,11H), 1.09-0.91 (m, 9H).

Step 2:

To a solution of tert-butyl4-tert-butyl-2-vinyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(550 mg, 1.62 mmol) in methanol (10 mL) was added Pd(OH)₂ (447 mg, 3.18mmol) and ammonium formate (2.19 g, 34.7 mmol) and the reaction mixtureheated at 55° C. for 20 min. The reaction mixture was filtered,concentrated to −10 mL and then diluted with dichloromethane and 1:1saturated NaHCO₃ solution/1M NaOH. The dichloromethane layer wasseparated and the aqueous layer extracted with dichloromethane (5×20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to provide tert-butyl8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(530 mg, 1.56 mmol, 96%) as a colorless oil. ESI-MS m/z calc. 340.3.found 341.3 (M+1)⁺; Retention time: 1.16 minutes (3 min run). ¹H NMR(400 MHz, DMSO-d₆) δ 3.59 (t, J=11.7 Hz, 2H), 3.48-3.36 (m, 1H), 3.11(br s, 1H), 2.91 (br s, 1H), 2.80 (d, J=10.7 Hz, 1H), 2.71 (dd, J=11.1,1.7 Hz, 1H), 2.23 (d, J=14.0 Hz, 1H), 1.81 (d, J=11.1 Hz, 1H), 1.71 (t,J=10.6 Hz, 1H), 1.39 (s, 9H), 1.38-1.22 (m, 5H), 0.96 (s, 9H), 0.89 (t,J=7.4 Hz, 3H).

Step 3:

Tert-butyl8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(530 mg, 1.56 mmol) was dissolved in dichloromethane and treated with asolution of HCl in dioxane (8.0 mL of 4 M, 33 mmol) and stirred for 15min. The reaction mixture was diluted with dichloromethane and washedwith 1:1 saturated NaHCO₃/1 M NaOH. The organic layer was dried overNa₂SO₄, filtered and concentrated to provide8-tert-butyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecane (390 mg, 99%)as an oily solid. ESI-MS m/z calc. 240.2. found 241.3 (M+1)⁺; Retentiontime: 0.21 minutes (3 min run).

Preparation of4-tert-butyl-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To tert-butyl4-tert-butyl-2-vinyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate(1.00 g, 2.95 mmol) and 4-methylmorpholine 4-oxide (381 mg, 3.25 mmol)in acetone (9.0 mL) and water (1.0 mL) was added a solution of osmiumtetroxide in 2-methyl-2-propanol (370 μL of 2.5% w/w, 0.0295 mmol) andthe solution stirred 2 h. The reaction quenched with 300 mL of 1 Msodium bisulfite and stirred for 5 min. The mixture was extracted withethyl acetate (2×200 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to providetert-butyl8-tert-butyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateas a white foamy solid. The crude material was taken directly to thenext step. ESI-MS m/z calc. 372.3. found 373.3 (M+1)⁺; Retention time:0.83 minutes (3 min run).

Step 2:

To a solution of tert-butyl8-tert-butyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(1.10 g, 2.95 mmol) in tetrahydrofuran (22 mL) was added sodiumperiodate (1.58 g, 7.38 mmol) and water (8.0 mL), resulting in a thickwhite precipitate. The reaction mixture was heated at 40° C. for 3 h,then additional sodium periodate added (2.95 mmol) and the mixturestirred for 16 h. The reaction mixture was filtered through Celite andrinsed with tetrahydrofuran (30 mL). The filtrate solution was cooled to0° C. and treated portion-wise with sodium borohydride (223 mg, 5.91mmol) over 5 min. The reaction mixture was stirred for 30 min thendiluted with brine (400 mL) and ethyl acetate (400 mL). The organicphase was separated and the aqueous phase extracted with ethyl acetate(3×100 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. Silica gel chromatography (80 g silica, 1-10%methanol/dichloromethane) provided tert-butyl8-tert-butyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(720 mg, 2.10 mmol, 71%) as colorless oil. ESI-MS m/z calc. 342.3. found343.5 (M+1)⁺; Retention time: 0.89 minutes (3 min run).

Step 3:

To a solution of tert-butyl8-tert-butyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(720 mg, 2.10 mmol) in N,N-dimethylformamide (7.0 mL) was added sodiumhydride (588 mg, 14.7 mmol) and the reaction stirred for 10 min. Methyliodide (916 μL, 14.7 mmol) was added and the reaction mixture stirredfor 20 min. The reaction was quenched with saturated aqueous NH₄Cl andextracted with ethyl acetate (2×25 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to provide tert-butyl8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(732 mg, 2.05 mmol, 98%). ESI-MS m/z calc. 356.3. found 357.3 (M+1)⁺;Retention time: 0.97 minutes (3 min run).

Step 4:

Tert-butyl8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(732 mg, 2.05 mmol) was dissolved in dichloromethane (10 mL) and treateddropwise with a solution of HCl in dioxane (12.8 mL of 4 M, 51.3 mmol).The reaction was stirred for 1.5 h and then diluted withdichloromethane. The organic phase was washed with 1:1 saturatedNaHCO₃/1 M NaOH, dried over Na₂SO₄ and concentrated to provide8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane (526mg, 2.05 mmol, 99%) as a viscous amber colored oil. ESI-MS m/z calc.256.2. found 257.3 (M+1)⁺; Retention time: 0.2 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 3.88-3.71 (m, 1H), 3.43-3.38 (m, 1H), 3.37 (d,J=2.5 Hz, 3H), 3.35-3.30 (m, 1H), 3.24 (td, J=12.2, 3.4 Hz, 1H),3.15-3.07 (m, 1H), 3.02 (td, J=12.2, 3.0 Hz, 1H), 2.93-2.84 (m, 1H),2.78-2.68 (m, 1H), 2.58 (d, J=8.9 Hz, 2H), 2.48-2.19 (m, 1H), 1.97 (d,J=11.4 Hz, 1H), 1.92 (ddd, J=16.6, 12.2, 9.6 Hz, 2H), 1.84-1.74 (m, 1H),1.70-1.55 (m, 2H), 1.00 (s, 9H).

Preparation of4-(2,2-difluoropropyl)-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane

Step 1:

To a mixture of tert-butyl10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate andK₂CO₃ (115 mg, 0.832 mmol) in acetonitrile (1.4 mL) was added1-bromopropan-2-one (304 mg, 2.00 mmol). The reaction mixture was heatedunder argon in a sealed tube for 16 h. The mixture was cooled, dilutedwith dichloromethane and washed with water. The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to provide tert-butyl2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate.ESI-MS m/z calc. 356.2. found 357.3 (M+1)⁺; Retention time: 0.98 minutes(3 min run).

Step 2:

To a solution of tert-butyl2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylatein dichloromethane (1 mL) was added and N,N-diethylaminosulfurtrifluoride (195 μL, 1.47 mmol). Cesium fluoride (9.0 mg, 0.059 mmol)was then added in two portions followed by trifluoroacetic acid (5 μL,0.06 mmol). The reaction was stirred for 15 min then cooled to 0° C. andquenched with 5 mL of saturated aqueous NaHCO₃. The reaction was dilutedwith dichloromethane (5 mL) and the layers separated. The organic layerwas washed with water, dried over Na₂SO₄, filtered and concentrated invacuo to provide tert-butyl8-(2,2-difluoropropyl)-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateas yellow oil. ESI-MS m/z calc. 378.2. found 379.3 (M+1)⁺; Retentiontime: 1.53 minutes (3 min run).

Step 3:

Tert-butyl8-(2,2-difluoropropyl)-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(77.0 mg, 0.204 mmol) was treated with HCl in dioxane (509 μL of 4 M,2.04 mmol) and stirred for 2 h. The solvent was evaporated to provide4-(2,2-difluoropropyl)-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecanehydrochloride as yellow solid (64 mg, 0.20 mmol, 99%). ESI-MS m/z calc.278.2. found 279.3 (M+1)⁺; Retention time: 0.79 minutes (3 min run).

Preparation of 5-Isopropoxy-6-methylpicolinic acid

Step 1:

2-Methyl-3-pyridinol (8.3 g, 76.1 mmol) was suspended in acetonitrile(125 mL). A solution of NBS (27.7 g, 155.6 mmol) in acetonitrile (275mL) was added to the suspension dropwise over 1 hour. The reactionmixture was heated at reflux for 1.5 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography using dichloromethane as eluent to give4,6-dibromo-2-methylpyridin-3-ol (15.8 g, 78%) as a yellow solid. ¹H NMR(300 MHz, DMSO) 2.41 (s, 3H), 7.70 (s, 1H), 9.98 (s, 1H).

Step 2:

4,6-Dibromo-2-methylpyridin-3-ol (15.8 g, 59.4 mmol) was dissolved inTHF (200 mL). The solution was cooled to −78° C. and n-BuLi (50 mL, 125mmol, 2.5 M in hexane) was added dropwise keeping the temperature below−78° C. The reaction mixture was allowed to stir at that temperature for2 hours. The reaction mixture was quenched with water (50 mL) and wasneutralized with 2 N HCl. The aqueous mixture was extracted withdichloromethane (2 times). The combined organic layers were dried(Na₂SO₄) and concentrated in vacuo to give 6-bromo-2-methylpyridin-3-ol(10.5 g, 95%) as a yellow oil. ¹H-NMR (300 MHz, DMSO) 2.29 (s, 3H), 7.08(d, 1H), 7.26 (d, 1H), 10.08 (s, 1H).

Step 3:

6-Bromo-2-methylpyridin-3-ol (10.5 g, 55.9 mmol) was dissolved in DMF(100 mL). K₂CO₃ (19.3 g, 139.6 mmol) and 2-bromopropane (13.1 ml, 139.6mmol) were added to the solution and the reaction mixture was heated at100° C. overnight. The reaction mixture was poured onto a mixture ofwater and EtOAc (200 mL). The layers were separated and the aqueouslayer was extracted with EtOAc (2×). The combined organic layers weredried (Na₂SO₄) and concentrated in vacuo. The crude oil was purified bysilica gel column chromatography (0-20% ethyl acetate/heptanes) to give6-bromo-3-isopropoxy-2-methylpyridine (10.9 g, 85%) as a yellow oil.¹H-NMR (300 MHz, CDCl₃) 1.42 (d, 6H), 2.48 (s, 3H), 4.65 (m, 1H), 7.20(d, 1H), 8.04 (d, 1H).

Step 4:

6-Bromo-3-isopropoxy-2-methylpyridine (2.00 g, 8.70 mmol), PdCl₂(PPh₃)₂(0.18 g, 0.26 mmol) and Et₃N (1.8 ml, 13.04 mmol) were added to MeOH(5.2 mL) and acetonitrile (20 mL) in a Berghoff reactor. The reactor wascharged with 10 bar CO (g) and was heated at 60° C. overnight. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between DCM and water. The layers were separated and theorganic layer was washed with brine and dried (Na₂SO₄). The mixture wasconcentrated in vacuo and purified by silica gel column chromatographyto give methyl 5-isopropoxy-6-methylpicolinate (1.3 g, 71%) as a yellowoil. ¹H-NMR (300 MHz, CDCl₃) 1.40 (d, 6H), 2.53 (s, 3H), 3.98 (s, 3H),4.62 (m, 1H), 7.12 (d, 1H), 7.98 (d, 1H).

Step 5:

5-Isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was dissolved inTHF/water 2:1 (9 mL). LiOH*H₂O (0.26 g, 6.22 mmol) was added and thereaction mixture was stirred at room temperature overnight. The mixturewas poured into a mixture of water and EtOAc and the layers wereseparated. The aqueous layer was acidified to pH 4 with 2 N HCl and wasextracted with EtOAc (2×). The combined organics were dried (Na₂SO₄) andconcentrated in vacuo to give 5-isopropoxy-6-methylpicolinic acid (860mg, 74%) as a beige solid. ¹H-NMR (300 MHz, DMSO) 1.31 (d, 6H), 4.73 (m,1H), 7.44 (d, 1H), 7.86 (d, 1H).

Preparation of 4-(1-Hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid

4-Bromo-3-methylbenzoic acid (3.96 g, 18.4 mmol) was dissolved intetrahydrofuran (100 mL) and the solution was cooled to −78° C.n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwiseover 20 minutes. The reaction mixture was allowed to stir for 30 minutesat −78° C. and then acetone (1.35 mL, 18.4 mmol) was added in a dropwisemanner. The reaction mixture was allowed to stir for 30 minutes at −78°C., and then allowed to warm to room temperature. The reaction mixturewas then diluted with 1M aqueous sodium hydroxide (100 mL). The organiclayer was discarded and then the aqueous layer was acidified with 4Maqueous hydrochloric acid. The aqueous layer was then extracted 3 timeswith ethyl acetate. The combined extracts were dried over sodium sulfateand then concentrated in vacuo. The crude material was purified bysilica gel column chromatography using a gradient of 0-10% methanol indichloromethane to give 4-(1-hydroxy-1-methyl-ethyl)-3-methyl-benzoicacid (1.51 g, 42%). ¹H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 7.68 (dd,J=3.9, 2.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H),1.51 (s, 6H).

Preparation of 4-(2-Methoxyethoxy)-3-methylbenzoic acid

To a solution of 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13 mmol) in THF(24 mL) was added tetrabutylphosphonium hydroxide (18 mL of 40% w/v, 26mmol). The reaction mixture was cooled to 0° C. and then1-bromo-2-methoxy-ethane (1.8 g, 1.2 mL, 13 mmol) was added. Thereaction mixture was allowed to warm to room temperature overnight. Thereaction mixture was acidified using 1M HCl and the aqueous layer wasextracted with ethyl acetate. The organics were dried over sodiumsulfate and concentrated in vacuo to yield4-(2-methoxyethoxy)-3-methylbenzoic acid (182 mg, 6%). ESI-MS m/z calc.210.2. found 209.2 (M-H)⁻; Retention time: 0.96 minutes (3 min run).

The following compound was synthesized using the procedures describedabove: 4-(3-methoxypropoxy)-3-methylbenzoic acid.

Preparation of 4-tert-Butoxy-3-methoxybenzoic acid

Step 1:

4-Hydroxy-3-methoxy-benzaldehyde (500 mg, 3.29 mmol), Boc₂O (1.74 g,7.97 mmol), and Sc(OTf)₃ (80 mg, 0.16 mmol) were combined indichloromethane (5 mL). The reaction mixture was allowed to stir at roomtemperature for 24 hours. Water (5 mL) and dichloromethane (5 mL) wereadded and the two phases were separated. The aqueous layer was extractedwith dichloromethane (3×5 mL) and the combined organics were stirredwith 10% aqueous potassium hydroxide until all remaining startingmaterial was not observed in the organic phase (TLC, 40% ethyl acetatein hexanes). The two phases were separated and the dichloromethane layerwas then washed twice with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentrated in vacuoto give 4-tert-butoxy-3-methoxybenzaldehyde (130 mg, 19%) as a yellowoil. ESI-MS m/z calc. 208.1. found 209.2 (M+1)⁺. Retention time: 0.96minutes (6 min run).

Step 2:

4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was suspended ina mixture of dioxane (520 μL) and potassium hydroxide (6.5 mL of 0.20 M,1.3 mmol). KMnO₄ (150 mg, 0.93 mmol) was added and the reaction wasstirred vigorously for 16 hours. The reaction mixture was filtered andthen concentrated in vacuo to 3 mL. Hydrochloric acid (1M, 4 mL) wasadded and the resulting precipitate was filtered and washed with 1M HCland a small amount of water to yield 4-tert-butoxy-3-methoxy-benzoicacid (68 mg, 49%) as a white solid. ESI-MS m/z calc. 224.1. found 225.2(M+1)⁺. Retention time: 1.66 minutes (3 min run). ¹H NMR (400 MHz, DMSO)δ 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 3.78 (s,3H), 1.32 (s, 9H).

Preparation of 3-Methoxy-4-(2-methoxy-2-methylpropoxy)benzoic acid

Step 1:

To a stirred solution of methyl 4-hydroxy-3-methoxy-benzoate (2 g, 10.98mmol), 2-methylprop-2-en-1-ol (871.0 mg, 1.0 mL, 12.1 mmol) andtriphenylphosphine (3.17 g, 2.8 mL, 12.1 mmol) in THF (63.28 mL) at 0°C. was added DIAD (2.44 g, 2.34 mL, 12.1 mmol). The ice bath was removedand the reaction was stirred at 55° C. for 16 hours. The reactionmixture was diluted with EtOAc and washed sequentially with NaHCO₃ (2×20mL) and brine (2×20 mL) solutions. The organic layer was separated,dried over Na₂SO₄, filtered and the solvent was evaporated under reducedpressure. The crude product was purified with silica gel using (0-30%)ethyl acetate-hexanes to yield methyl3-methoxy-4-(2-methylallyloxy)benzoate (1.94 g, 75%) as a viscousliquid. ESI-MS m/z calc. 236.1. found 237.1 (M+1)⁺. Retention time: 1.63minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.56 (dd, J=8.4, 2.0 Hz,1H), 7.47 (d, J=1.9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.07 (br s, 1H),4.97 (br s, 1H), 4.55 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 1.78 (s, 3H).

Step 2:

To methyl 3-methoxy-4-(2-methylallyloxy)benzoate (313 mg, 1.33 mmol) inMeOH (2.5 mL) was added H₂SO₄ (71 μL, 1.3 mmol) and the reaction mixturewas heated in a microwave vial at 100° C. for 15.5 hours. The reactionmixture was concentrated in vacuo and the crude product was purified bysilica gel column chromatography using 0-30% ethyl acetate in hexane aseluent to yield methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate(208 mg, 59%). ESI-MS m/z calc. 268.1. found 269.5 (M+1)⁺; Retentiontime: 1.46 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.57 (dd,J=8.4, 2.0 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 3.90(s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).

Step 3:

Methyl 3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoate (177 mg, 0.66mmol), dioxane (1.9 mL) and NaOH (1.8 mL of 1 M, 1.80 mmol) werecombined and the reaction mixture was heated at 80° C. for 15 minutes.The reaction mixture was concentrated in vacuo and the crude mixture wasdissolved in water. The mixture was washed with EtOAc (3×). The aqueouslayer was acidified with 1N HCl then washed with EtOAc (3×). Thecombined organic layers was dried over Na₂SO₄, filtered and the solventwas evaporated under reduced pressure to yield3-methoxy-4-(2-methoxy-2-methyl-propoxy)benzoic acid (130 mg, 77%).ESI-MS m/z calc. 254.1. found 255.5 (M+1)⁺; Retention time: 1.14 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 7.54 (dd, J=8.4,1.9 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 3.89 (s,2H), 3.81 (s, 3H), 3.17 (s, 3H), 1.22 (s, 6H).

Preparation of 4-(2-Hydroxypropan-2-yl)-3-methoxybenzoic acid

4-Bromo-3-methoxy-benzoic acid (2.00 g, 8.67 mmol) was dissolved in THF(50 mL) and the solution was cooled to −78° C. n-BuLi in hexanes (7.6 mLof 2.5 M, 19 mmol) was added dropwise over 15 minutes. The reactionmixture was allowed to stir for 30 minutes at −78° C. and then acetone(640 μL, 8.9 mmol) was added in a dropwise manner. The reaction mixturewas allowed to stir for 30 minutes at −78° C., and then it was allowedto warm to room temperature. The reaction mixture was then diluted with100 mL of 1M aqueous sodium hydroxide (100 mL). The organic layer wasdiscarded and the aqueous layer was made acidic with 4M aqueoushydrochloric acid. The aqueous layer was then extracted 3 times withethyl acetate. The combined extracts were dried over sodium sulfate andthen evaporated to dryness. The crude material was purified by columnchromatography using 0-5% methanol in dichloromethane as eluent to give4-(2-hydroxypropan-2-yl)-3-methoxybenzoic acid (618 mg, 34%). ESI-MS m/zcalc. 210.1. found 209.1 (M−1)⁻; Retention time: 0.68 minutes (3 minrun).

Preparation of 4-(Isopropylsulfonyl)-3-methylbenzoic acid

Step 1:

Butyllithium (16 mL of 1.6 M, 25.6 mmol) was added dropwise to a mixtureof 4-bromo-3-methyl-benzoic acid (2.5 g, 11.6 mmol) and THF (63 mL) at−78° C. The reaction mixture was allowed to stir at −78° C. for 30minutes before a solution of 2-isopropyldisulfanylpropane (1.7 g, 11.6mmol) in THF (2 mL) was added dropwise. The mixture was allowed to stirat −78° C. for 30 minutes, then 30 minutes at room temperature. Thereaction mixture was then diluted with 1M aqueous sodium hydroxide (100mL). The organic layer was discarded and the aqueous layer was acidifiedwith 4M aqueous hydrochloric acid. The aqueous layer was then extracted3 times with ethyl acetate. The combined extracts were dried over sodiumsulfate and concentrated in vacuo. The crude material was purified bysilica gel column chromatography using a gradient of 0-5% MeOH indichloromethane to give 4-(isopropylthio)-3-methylbenzoic acid (873 mg,18%). MS m/z calc. 210.3. found 211.2 (M+1)⁺. Retention time: 2.32minutes (3 min run).

Step 2:

3-Chlorobenzenecarboperoxoic acid (933 mg, 4.2 mmol) was added to amixture of 4-(isopropylthio)-3-methylbenzoic acid (250 mg, 1.2 mmol) anddichloromethane (5 mL) at 25° C. The reaction mixture was allowed tostir at 25° C. for 2 hours, then concentrated in vacuo. The white solidmaterial was taken up in dichloromethane and was subjected to silica gelcolumn chromatography (0-2% MeOH/dichloromethane) to give4-isopropylsulfonyl-3-methyl-benzoic acid (90 mg, 31%) as a white solid.ESI-MS m/z calc. 242.3. found 243.2 (M+1)⁺. Retention time: 1.57 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 13.50 (s, 1H), 8.50-7.66 (m, 3H),3.50-3.47 (m, 1H), 2.67 (s, 3H), 1.19 (d, J=1.16 Hz, 6H).

Preparation of 3-Chloro-4-isopropoxybenzoic acid

Step 1:

To a solution of 3-chloro-4-hydroxy-benzoic acid (1.0 g, 5.8 mmol) inmethanol (30 mL) was added sulfuric acid (3 mL, 56.3 mmol) and themixture was stirred at 60° C. for 12 hours. The reaction mixture wascooled to room temperature and the methanol was removed in vacuo. Theresidue was partitioned between a saturated solution of K₂CO₃ and ethylacetate (3×30 mL), dried, filtered and concentrated in vacuo to yieldmethyl 3-chloro-4-hydroxy-benzoate (0.9 g, 83%) as a white solid. ESI-MSm/z calc 186.5. found 187.5 (M+1)⁺; Retention time: 1.17 minutes (3 minrun). ¹H NMR (400.0 MHz, CDCl₃) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd,J=8.8, 2.2; H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H).

Step 2:

To methyl 3-chloro-4-hydroxy-benzoate (3.0 g, 16.1 mmol) in DMF (19 mL)was added potassium carbonate (8.9 g, 64.3 mmol) followed by2-iodopropane (5.5 g, 3.2 mL, 32.2 mmol). The reaction mixture washeated at 60° C. for 1.5 hours. The reaction mixture was cooled,filtered and diluted with EtOAc and the solvent was concentrated invacuo. The material was dissolved in EtOAc and washed with water (3×10mL) and brine (1×10 mL). The organic layer was dried over Na₂SO₄,filtered and the solvent was removed in vacuo to give methyl3-chloro-4-isopropoxybenzoate. To the ester was added dioxane (47 mL)and sodium hydroxide (42.7 mL of 1 M, 42.7 mmol) and the reaction washeated at 80° C. for 15 minutes. The reaction was cooled and solvent wasremoved in vacuo. The resulting residue was dissolved in water andwashed with EtOAc (3×10 mL) and the layers were separated. The aqueouslayer was acidified to pH 1 and was extracted with EtOAc (3×10 mL). Theorganic layer was separated and dried over Na₂SO₄, filtered and thesolvent was removed in vacuo to yield 3-chloro-4-isopropoxy-benzoic acid(2.86 g, 83%) as a white solid. ESI-MS m/z calc. 213.6. found 215.3(M+1)⁺; Retention time: 1.51 minutes (3 min run). ¹H NMR (400.0 MHz,CDCl₃) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2; H, 1H), 7.06(d, J=8.8 Hz, 1H) and 3.90 (s, 3H) ppm.

Preparation of 4-isopropoxy-3-methyl-benzoic acid

Step 1:

To a solution of 4-hydroxy-3-methylbenzoic acid (10.0 g, 65.7 mmol) andDMF (100 μL) in methanol (35 mL) was added dropwise thionyl chloride(7.8 g, 4.8 mL, 65.7 mmol). The reaction mixture was allowed to stir atroom temperature for 2 hours. The reaction mixture was quenched with theaddition of aqueous saturated sodium bicarbonate solution (50 mL) andmethanol was removed in vacuo. The aqueous layer was then extracted withEtOAc (3×50 mL). The organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to provide methyl4-hydroxy-3-methyl-benzoate (10.5 g, 96%) as a light brown solid. ESI-MSm/z calc. 166.4. found 167.4 (M+1)⁺; Retention time: 1.09 minutes (3 minrun).

Step 2:

To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol)followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reactionmixture was heated at 60° C. for 2 hours. The reaction mixture wascooled and diluted with ether (350 mL), and filtered over celite. Thefiltrate was washed with water (3×100 mL) and brine (100 mL) solution.The layers were separated and organics were dried over MgSO₄. Thesolvent was evaporated and resulting residue was purified by silica gelusing 0-30% EtOAc/hexanes mixtures as eluent to give methyl4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MSm/z calc. 208.25. found 209.2 (M+1)⁺; Retention time: 1.93 minutes (3min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solutionof methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) intetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidlystirred and heated at 65° C. for 6 hours. The reaction mixture wascooled, diluted with water (75 mL) and extracted with ether (2×50 mL).The aqueous layer was acidified to pH 2 with 6N aq. HCl and extractedwith ethyl acetate (4×75 mL). The combined organics were washed withwater (75 mL) and brine solution (75 mL) and layers were separated. Theorganics were dried over MgSO₄ and concentrated in vacuo to give4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals.ESI-MS m/z calc. 194.2. found 195.3 (M+1)⁺; Retention time: 1.53 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz,6H).

Preparation of 4-(2-Methoxy-2-methyl-propoxy)benzoic acid

Step 1:

A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL),4-hydroxybenzonitrile (2.0 g, 16.8 mmol), potassium carbonate (9.3 g,67.3 mmol), water (6 mL) and ethanol (60 mL) was heated at 80° C.overnight. The reaction mixture was cooled, concentrated in vacuo andresidue was diluted with ether (200 mL) and filtered. The filtrate waswashed with water (50 mL) and brine solution (50 mL). The organics wereseparated and dried over MgSO₄ and purified by silica gel columnchromatography using 0-100% EtOAc/DCM as eluent to give4-(2-hydroxy-2-methyl-propoxy)benzonitrile (3.0 g, 94%) as a yellowsolid. ESI-MS m/z calc. 191.1. found 192.3 (M+1)⁺; Retention time: 1.05minutes (3 min run).

Step 2:

To 4-(2-hydroxy-2-methyl-propoxy)benzonitrile (1 g, 5.2 mmol) in DMF (10mL) was added sodium hydride (220 mg, 5.5 mmol) and the reaction mixturewas stirred for 20 minutes. Iodomethane (816 mg, 358 μL, 5.8 mmol) wasadded and the reaction mixture was stirred for 1 hour at roomtemperature and 1 hour at 50° C. The reaction mixture was cooled anddiluted with ether (250 mL) and washed with water (3×50 mL) and brine(50 mL) solution. The organics were separated and dried over MgSO₄ andconcentrated in vacuo to give 4-(2-hydroxy-2-methylpropoxy)benzonitrile.ESI-MS m/z calc. 205.2. found 206.3 (M+1)⁺; Retention time: 1.38 minutes(3 min run). To 4-(2-hydroxy-2-methylpropoxy)benzonitrile in ethanol (15mL) was added sodium hydroxide (5.3 mL of 5 M, 26.1 mmol) and reactionwas heated at 85° C. for 2 hours. The reaction mixture was cooled andconcentrated in vacuo, then diluted with ethyl acetate (50 mL) and 3NHCl solution was added to adjust to pH 2 and the layers were separated.The aqueous layer was extracted with ethyl acetate (3×50 mL). Thecombined organics were washed with brine solution (2×50 mL), dried overMgSO₄ and concentrated in vacuo to give4-(2-methoxy-2-methyl-propoxy)benzoic acid (0.9 g, 77%) as a whitesolid. ESI-MS m/z calc. 224.2. found 225.3 (M+1)⁺; Retention time: 1.15minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 7.98-7.73 (m, 2H),7.10-6.90 (m, 2H), 3.90 (d, J=8.4 Hz, 2H), 3.15 (d, J=3.8 Hz, 3H), 1.19(d, J=15.0 Hz, 6H).

Preparation of 4-(2-Hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid

A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL),4-hydroxy-3-methyl-benzoic acid (2.0 g, 13.15 mmol), potassium carbonate(7.3 g, 52.71 mmol), water (6 mL) and ethanol (60 mL) was heated at 80°C. for 16 hours. The reaction mixture was cooled to room temperature andpartitioned between 1N NaOH and EtOAc and the layers were separated. Theorganic layer was washed with 1N NaOH (2×10 mL) and the combined aqueouslayers were washed with EtOAc. The combined organic layers were driedand concentrated in vacuo to give ethyl4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoate. The ester wasdissolved in ethanol (15 mL) and water (2 mL), sodium hydroxide (1.1 g,26.30 mmol) was added and the reaction mixture was stirred at 40° C. for4 hours. The reaction mixture was poured into 1N NaOH solution andextracted with ether (2×10 mL). The aqueous layer was acidified to pH2-3 using 6N HCl solution and extracted with EtOAc (3×10 mL). Theorganics were separated and washed with brine solution. The organiclayer was dried (Na₂SO₄) and concentrated in vacuo and the resultingmaterial was triturated with ether to give4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75%) as awhite solid. ESI-MS m/z calc. 224.1. found 225.5 (M+1)⁺; Retention time:1.06 minutes (3 min run) ¹H NMR (400 MHz, DMSO) δ 7.75 (dd, J=8.5, 2.0Hz, 1H), 7.73-7.70 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.67 (s, 1H, OH),3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H).

Preparation of 5-Isopropoxypyridine-2-carboxylic acid

Step 1:

To a solution of 5-hydroxypyridine-2-carboxylic acid (1.0 g, 7.2 mmol)in methanol (15 mL) was added sulfuric acid (881 μL, 16.53 mmol)dropwise and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, diluted withDCM (100 mL), washed with sat. aq NaHCO₃ solution. The organic layer wasseparated and dried with sodium sulfate, filtered and concentrated invacuo to give methyl 5-hydroxypyridine-2-carboxylate, which was usedwithout further purification. ESI-MS m/z calc. 150.1. found 154.1(M+1)⁺; Retention time: 0.33 minutes (3 min run).

Step 2:

To methyl 5-hydroxypyridine-2-carboxylate (0.6 g, 3.92 mmol) in DMF (3.6mL) was added potassium carbonate (2.2 g, 15.7 mmol) followed by2-bromopropane (736 μL, 7.8 mmol) The reaction mixture was heated at 60°C. for 1.5 hours. The reaction mixture was cooled and filtered usingEtOAc and the solvent was evaporated under reduced pressure. The residuewas dissolved in EtOAc and washed with water (3×10 mL) and brinesolution (10 mL). The organics were separated and dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography using 0-50% EtOAc:hexanes as eluent to givemethyl 5-isopropoxypyridine-2-carboxylate (555 mg, 73%) as a colorlessoil. ESI-MS m/z calc. 195.1. found 196.3 (M+1)⁺; Retention time: 1.09minutes (3 min run). Lithium hydroxide (5.7 mL of 2 M, 11.37 mmol) wasadded to a solution of methyl 5-isopropoxypyridine-2-carboxylate (555mg, 2.84 mmol) in dioxane (4 mL) and stirred at 55° C. for 2 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand layers were separated. The aqueous layer was acidified with 1N HClsolution and extracted with ethyl acetate. The organics were separatedand dried over sodium sulfate, filtered and concentrated in vacuo togives-isopropoxypyridine-2-carboxylic acid (150 mg, 29%). ESI-MS m/zcalc. 182.1. found 182.3 (M+1)⁺; Retention time: 0.33 minutes (3 minrun).

Preparation of 2-Fluoro-4-isopropoxy-benzoic acid

Step 1:

To a solution of 2-fluoro-4-hydroxy-benzoic acid (5.32 g, 34.1 mmol) inmethanol (21 mL) was added thionyl chloride (4.86 g, 3 mL, 40.9 mmol)dropwise and the reaction mixture was stirred at 40° C. for 3 hours. Thereaction mixture was concentrated in vacuo and diluted with DCM (100 mL)and washed with aqueous saturated NaHCO₃ (2×50 mL) solution. Theorganics were separated and dried with MgSO₄, filtered and concentratedin vacuo to give methyl 2-fluoro-4-hydroxy-benzoate (2.3 g, 40%). ESI-MSm/z calc. 170.1. found 171.3 (M+1)⁺; Retention time: 0.84 minutes (3 minrun).

Step 2:

To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol),potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at60° C. for 2 hours. The reaction was cooled and diluted with ether (50mL) and filtered over Celite®. The filtrate was washed sequentially withwater (3×25 mL) and brine solution (25 mL). The organic layer wasseparated and dried over MgSO₄ and solvent was concentrated in vacuo togive a residue which was purified by silica gel column chromatographyusing 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoateas a colorless oil (2.2 g, 83%). To a solution of methyl2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) wasadded a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5mL). The reaction mixture was stirred at 70° C. for 2 hours. Thereaction mixture was cooled to room temperature and the excess LiOH wasremoved by filtration. The filtrate was diluted with water (9 ml), andwashed with ether (2×5 mL). The aqueous layer was separated and cooledto 0° C. and the pH was adjusted to pH 2 by addition of 6 M HClsolution. The aqueous layer was extracted with EtOAc (3×30 mL). Theorganics were separated and washed sequentially with water and brine.The organic layer was separated, dried and concentrated in vacuo to give2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9,2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).

Preparation of 3-Methyl-4-(oxetan-3-yloxy)benzoic acid

Step 1:

To a solution of 4-hydroxy-3-methylbenzoic acid (10.00 g, 65.7 mmol) andDMF (100 μL) in MeOH (35 mL) was added dropwise thionyl chloride (4.8mL, 65.7 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was quenched with theaddition of aqueous saturated sodium bicarbonate solution (50 mL), andmethanol was removed under reduced pressure. The residue was extractedwith EtOAc (3×50 mL) and dried over sodium sulfate, filtered andconcentrated in vacuo to provide methyl 4-hydroxy-3-methyl-benzoate(10.53 g, 96%) as a light brown solid. ESI-MS m/z calc. 166.0. found167.1 (M+1)⁺; Retention time: 1.09 minutes (3 min run).

Step 2:

To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours.The reaction was cooled and quenched with brine solution and extractedwith EtOAc (3×10 mL). The organic layer was separated and dried oversodium sulfate and evaporated to give methyl3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1hour. The reaction was acidified with 1 M HCl solution to pH 3 andextracted with EtOAc. The organics were separated and dried andconcentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid.ESI-MS m/z calc. 208.1. found 209.3 (M+1)⁺; Retention time: 1.04 minutes(3 min run).

Preparation of 4-Ethylsulfonyl-3-methyl-benzoic acid

Step 1:

To a solution of 4-fluoro-3-methyl-benzoic acid (27.4 g, 178.0 mmol) inmethanol (200 mL) was slowly added thionyl chloride (17.8 mL, 243.3mmol). The solution was stirred at 35° C. for 7 hours. The solution wasallowed to cool to room temperature and concentrated in vacuo to an oil.This oil was dissolved in EtOAc (75 mL) and washed sequentially withsaturated aqueous sodium bicarbonate solution (2×75 mL) and brinesolution (1×75 mL). The organic layer was separated and dried oversodium sulfate, filtered and concentrated in vacuo to provide methyl4-fluoro-3-methyl-benzoate (25.4 g, 85%) as a red oil. ESI-MS m/z calc.168.0. found 169.2 (M+1)⁺; Retention time: 1.48 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 7.92-7.88 (m, 1H), 7.88-7.83 (m, 1H), 7.04 (t,J=8.9 Hz, 1H), 3.90 (s, 3H), 2.31 (d, J=2.0 Hz, 3H).

Step 2:

To methyl 4-fluoro-3-methyl-benzoate (8.0 g, 47.6 mmol) in DMF (64 mL)was added ethylsulfanylsodium (10.0 g, 118.9 mmol) and the reaction washeated for 16 hours at 55° C. The reaction mixture was cooled to roomtemperature and quenched with brine solution and stirred for 20 minutes.The reaction mixture was extracted with EtOAc (3×10 mL). The aqueouslayer was treated with Clorox® bleach solution (150 mL) and the reactionmixture immediately turned colorless. The reaction mixture was stirredfor 10 minutes. The reaction was treated with 1N HCl solution to pH 1and extracted with EtOAc (3×10 mL). The organics were separated andwashed with brine solution (3×10 mL). The organic layer was dried oversodium sulfate and the solvent was removed in vacuo to provide4-ethylsulfonyl-3-methyl-benzoic acid (9.4 g, 86%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.13 (dd, J=13.8, 8.3 Hz, 3H), 3.22 (q, J=7.4 Hz,2H), 2.79 (s, 3H), 1.31 (t, J=7.4 Hz, 3H).

Preparation of 4-Tert-butylsulfonylbenzoic acid

Step 1:

Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium(2.0 g, 17.8 mmol) were combined in N,N-dimethylformamide (10 mL). Thereaction mixture was heated to 80° C. for 2 hours. After this time, aprecipitate formed and N,N-dimethylformamide (15 mL) was added and thereaction mixture was stirred for an additional 20 hours at 80° C. Thereaction mixture was partitioned between ethyl acetate (100 mL) andwater (100 mL). The aqueous layer was acidified with 4M hydrochloricacid, extracted with ethyl acetate (2×). The combined extracts weredried over sodium sulfate, filtered, and concentrated in vacuo to yield4-(tert-butylthio)benzoic acid as a colorless oil. The oil was dissolvedin acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w, 52.0mmol) was added to the reaction mixture. The resulting mixture washeated to 80° C. for 2 hours. The reaction mixture was then allowed tocool to room temperature, and diluted with water (50 mL) and ethylacetate (100 mL). The aqueous layer was extracted with ethyl acetate.The combined ethyl acetate extracts were dried over sodium sulfate,filtered, and concentrated in vacuo to yield 4-tert-butylsulfonylbenzoicacid (2.2 g, 92%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 13.59 (s,1H), 8.18 (d, J=8.0 Hz, 2H), 7.94 (d, J=7.6 Hz, 2H), 1.25 (s, 9H);ESI-MS m/z calc. 242.1. found 241.3 (M−1)⁻; Retention time: 1.33 minutes(3 min run).

Preparation of 3-Fluoro-4-isopropoxy-5-methoxy-benzoic acid

A solution of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (250 mg, 1.5mmol) in DMF (2.5 mL) was treated with potassium carbonate (812 mg, 5.9mmol) and stirred for 30 minutes. 2-Iodopropane (500 mg, 2.9 mmol) wasadded over 10 minutes and reaction mixture was stirred for 20 hours. Thereaction mixture was partitioned between EtOAc and saturated aqueoussodium chloride solution. The organic layer was washed with saturatedsodium bicarbonate solution. The organic layer was separated and driedover sodium sulfate, filtered and concentrated in vacuo to give3-fluoro-4-isopropoxy-5-methoxybenzaldehyde. To the aldehyde was addedtert-butanol (6.7 mL) and 2-methylbut-2-ene (4 mL, 38.2 mmol) and thereaction mixture was cooled to 0° C. A solution of chlorite (345 mg, 3.8mmol) and sodium dihydrogen phosphate hydrate (527 mg, 3.8 mmol) inwater (6.7 mL) was added dropwise over 5 minutes, and the reactionmixture was stirred 30 minutes. The reaction mixture was warmed to roomtemperature and stirred for 12 hours. The reaction mixture was basifiedwith 1 N NaOH solution and extracted with ethyl acetate (2×50 mL). Theaqueous layer was acidified with 1 N HCl solution and extracted withEtOAc (4×50 mL). The combined organics were dried (Na₂SO₄), filtered,and concentrated in vacuo to afford3-fluoro-4-isopropoxy-5-methoxy-benzoic acid (190 mg, 56%) as a whitesolid. ESI-MS m/z calc. 228.0. found 229.3 (M−1)⁺; Retention time: 1.57minutes (3 min run).

Preparation of 4-(Cyclopropylsulfamoyl)benzoic acid

To 4-chlorosulfonylbenzoic acid (10.0 g, 45.3 mmol) in dichloromethane(350 mL) at 0° C. was added cyclopropanamine (15.5 g, 19 mL, 271.9mmol). The reaction mixture was allowed to warm to room temperature over16 hours. The solvent was evaporated under reduced pressure. The residuewas dissolved in water (150 mL) and acidified using hydrochloric acid.The aqueous layer was extracted with EtOAc (2×200 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated in vacuo togive 4-(cyclopropylsulfamoyl)benzoic acid (10.0 g, 92%) as a whitesolid. ESI-MS m/z calc. 241.0. found 242.5 (M+1)⁺; Retention time: 0.84minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.97 (d,J=8.3 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 2.03-1.90(m, 1H), 0.38-0.28 (m, 2H), 0.23-0.15 (m, 2H).

Preparation of 4-(3-Hydroxypropoxy)-3-methyl-benzoic acid

Step 1:

To a solution of methyl 4-hydroxy-3-methyl-benzoate (3.03 g, 18.2 mmol)in DMF (9 mL) was added 3-bromopropan-1-ol (3.80 g, 2.4 mL, 27.4 mmol)and cesium carbonate (17.8 g, 54.7 mmol) and the reaction mixture washeated at 60° C. for 16 hours. The reaction mixture was cooled to roomtemperature and then partitioned between water (250 mL) and ethylacetate (2×100 ml). The organic layers were combined, washed with brinesolution (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto yield a crude oil that was purified by silica gel columnchromatography eluting with EtOAc/hexanes (10-100%) to give methyl4-(3-hydroxypropoxy)-3-methyl-benzoate (1.87 g, 46%) as a white solid.ESI-MS m/z calc. 224.0. found 225.0 (M+1)⁺; Retention time: 1.27 minutes(3 min run); ¹H NMR (400 MHz, CDCl₃) δ 7.94-7.77 (m, 2H), 6.85 (d, J=8.5Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.98-3.82 (m, 5H), 2.24 (s, 3H), 2.10(p, J=5.9 Hz, 2H).

Step 2:

To a solution of methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (0.9 g,4.01 mmol) in dioxane (8 mL) was added 1N NaOH (5 mL) and the reactionmixture was heated at 70° C. for 22 hours. The solvent was concentratedin vacuo and the crude residue was dissolved in water (20 mL) andextracted with ethyl acetate (1×20 mL). The aqueous layer was acidifiedwith 1 M HCl solution and extracted with ethyl acetate (2×20 mL). Theorganics were separated, dried with Na₂SO₄ and concentrated in vacuo togive 4-(3-hydroxypropoxy)-3-methyl-benzoic acid (0.7 g, 87%) as a whitesolid. ESI-MS m/z calc. 210.0. found 211.0 (M+1)⁺; Retention time: 0.95minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 12.5 (bs, 1H), 7.97-7.60(m, 2H), 7.01 (d, J=8.6 Hz, 1H), 4.57 (s, 1H), 4.11 (t, J=6.2 Hz, 2H),3.59 (t, J=5.5 Hz, 2H), 2.19 (s, 3H), 1.89 (p, J=6.2 Hz, 2H).

Preparation of 3-Fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid

Step 1:

4-Bromo-3-fluoro-benzoic acid (5.0 g, 22.8 mmol) was dissolved THF (60mL) and the solution was cooled to −78° C. n-Butyllithium (20 mL of 2.5M in hexanes, 50.2 mmol) was added dropwise and the mixture was allowedto stir for 1 minute at −78° C., then acetone (3.7 mL, 50.2 mmol) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred for 16 hours. The reaction mixture was quenchedwith sat. NH₄Cl solution, diluted with saturated citric acid solutionand the aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The desired compound was contaminated with3-fluoro-4-hydroxybenzoic acid and the mixture was taken forward withoutany purification. ESI-MS m/z calc. 198.2. found 197 (M−1)+; Retentiontime: 2.13 minutes (15 min run).

Step 2:

To a solution of 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (9.1g, 45.7 mmol) in DMF (40 mL) was added cesium carbonate (22.3 g, 68.5mmol) followed by benzyl bromide (11.7 g, 8.1 mL, 68.5 mmol) andreaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was partitioned between EtOAc and H₂O. The aqueouslayer was extracted with EtOAc (3×20 mL). The combined organic layerswere washed sequentially with H₂O (3×10 mL), brine solution. Theorganics were separated and dried over MgSO₄, filtered and concentratedin vacuo. The resulting residue was purified by silica gel columnchromatography eluting with 10-20% EtOAc-hexanes to provide benzyl3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 21%) ESI-MS m/zcalc. 288.2. found 289.3 (M+1)⁺; Retention time: 1.79 min (3 min run).To a solution of benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate(2.8 g, 9.71 mmol) in MeOH (50 mL) was added palladium on carbon (100mg, 0.09 mmol) and the reaction mixture was subjected to an atmosphereof hydrogen for 16 hours. The catalyst was removed via filtration overCelite® and the solvent removed in vacuo to provide3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (1.8 g, 96%) as awhite solid. ESI-MS m/z calc. 198.2. found 199.9 (M+1)⁺; Retention time:0.91 minutes (3 min run).

Preparation of 4-(2-Hydroxy-2-methyl-propyl)benzoic acid

Step 1:

A solution of bromo(methyl)magnesium in diethyl ether (25 mL of 3 M,74.5 mmol) in THF (8 mL) and toluene (25 mL) was added to a solution ofethyl 2-(4-bromophenyl)acetate (8.23 g, 33.9 mmol) in Et₂O (165 mL) andthe reaction mixture was stirred at 40° C. for 1 hour. The reactionmixture was quenched by the addition of saturated aqueous ammoniumchloride (200 mL) and the phases were separated. The organics were driedover sodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography eluting with0-30% EtOAc-hexanes to give 1-(4-bromophenyl)-2-methyl-propan-2-ol (5.68g, 73%), as a clear oil. ESI-MS m/z calc. 228.1. found 229.5 (M+1)⁺;Retention time: 1.45 minutes (3 min run).

Step 2:

1-(4-bromophenyl)-2-methyl-propan-2-ol (2.77 g, 12.1 mmol) was dissolvedin dry THF (30 mL) and the solution was cooled to −78° C.Tert-butyllithium in pentane (15 mL of 1.7 M, 25.4 mmol) was addeddropwise over 10 minutes and the reaction mixture was stirred at −78° C.for 2 hours. The reaction mixture was added via cannula to crushed solidCO₂ (53.2 g, 1.21 mol) in Et₂O under a flow of nitrogen gas. Thereaction mixture was allowed to warm to room temperature, diluted withEtOAc and washed with water. The aqueous phase was acidified (pH 2) with1N HCl solution and the aqueous layer was extracted with EtOAc. Theorganics were dried over sodium sulfate, filtered and concentrated invacuo to give 4-(2-hydroxy-2-methyl-propyl)benzoic acid (620 mg, 26%) asa white solid. ESI-MS m/z calc. 194.0. found 195.3 (M+1)⁺; Retentiontime: 0.93 minutes (3 min run).

Preparation of 3-Methyl-4-(oxetan-3-yl)benzoic acid

Step 1:

To (4-cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.90 mmol), nickeliodide (0.10 g, 0.33 mmol), (1S,2S)-2-aminocyclohexan-1-ol (0.05 g, 0.33mmol) and NaHMDS (2.01 g, 10.90 mmol) in isopropanol (10 mL) under anatmosphere of nitrogen was added 3-iodooxetane (1.00 g, 5.40 mmol) inisopropanol (1 mL) via cannula. The reaction mixture was heated at 90°C. for 2 hours, then cooled, diluted with ethanol (20 mL) and filteredover Celite®. The filtrate was concentrated in vacuo, then the residuewas purified by silica gel column chromatography using 0-60%EtOAc/hexane as eluant to give 3-methyl-4-(oxetan-3-yl)benzonitrile(0.62 g, 65%) as a white solid. ESI-MS m/z calc. 173.1. found 174.3(M+1)⁺; Retention time: 1.09 minutes (3 min run).

Step 2:

To 3-methyl-4-(oxetan-3-yl)benzonitrile (500 mg, 2.89 mmol) in ethanol(7.5 mL) was added NaOH (3 mL of 5 M, 15.00 mmol) and the reactionmixture was heated at 85° C. for 1 hour. The reaction mixture was cooledto room temperature, concentrated in vacuo and diluted with ethylacetate (20 mL). 6N HCl solution (˜3 mL) was added until pH 6 wasreached, then the aqueous layer was extracted with ethyl acetate (2×20mL), and the combined organics were washed with brine solution (10 mL).The organics were separated, dried over MgSO₄ and concentrated in vacuoto give a white solid, which was triturated with ether to give a mixture(2:3 by NMR) of acid and amide. ESI-MS m/z (acid) calc. 192.1. found193.3 (M+1)⁺; Retention time: 0.88 minutes (3 min run). ESI-MS m/z(amide) calc. 191.1. found 192.3 (M+1)⁺; Retention time: 0.47 min (3 minrun).

Preparation of 2-(Difluoromethoxy)-3-fluoro-benzoic acid

Step 1:

To a solution of 3-fluoro-2-hydroxy-benzoic acid (5.0 g, 32 mmol) inmethanol (20 mL) was added thionyl chloride (5.0 g, 42 mmol) dropwiseand the reaction mixture was stirred at 40° C. for 3 hours, then heatedat 50° C. for 16 hours. The reaction mixture was cooled and concentratedin vacuo and resulting residue was purified by silica gel columnchromatography using 0-50% ethyl acetate/hexanes mixtures as eluant togive methyl 3-fluoro-2-hydroxy-benzoate (5.1 g, 94%) as white crystals.ESI-MS m/z calc. 170.0. found 170.9 (M+1)⁺; Retention time: 1.33 minutes(3 min run).

Step 2:

A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol),2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) andpotassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at120° C. for 5 hours. The reaction mixture was diluted with water (20 mL)and extracted with ether (2×10 mL). The organics were separated andwashed sequentially with water (5 mL) and brine solution (5 mL). Theorganics were dried (MgSO₄) and concentrated in vacuo to give residuewhich was purified by silica gel column chromatography using 0-30%EtOAc/hexanes as eluent to give methyl2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12%aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL).The aqueous layer was acidified to pH 1 with 6 N HCl solution to give asuspension. The solid was filtered and washed with water, then dried invacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) asan off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=7.8 Hz, 1H),7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t,J=74.4 Hz, 1H).

Preparation of 4-(1-Hydroxy-1-methyl-ethyl)benzoic acid

4-Isopropylbenzoic acid (5.0 g, 30.5 mmol) was dissolved in a solutionof potassium hydroxide (4.1 g, 2 mL, 73.1 mmol) in water (125 mL). Tothe reaction mixture was added a solution of potassium permanganate (9.6g, 60.9 mmol) in water (125 mL). The combined mixture was allowed tostir at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. andtreated with ethylene glycol (100 μL) and cooled to 0° C. The solid wereremoved by filtration and the filtrate was acidified to pH 1 by additionof 6 N HCl solution. The solid was removed by filtration, and thefiltrate was extracted with diethyl ether (3×200 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated in vacuo to provide 4-(1-hydroxy-1-methyl-ethyl)benzoicacid (5.1 g, 93%) as a white solid. ESI-MS m/z calc. 180.1. found 181.2(M+1)⁺; Retention time: 0.6 minutes (3 min run). ¹H NMR (400 MHz, MeOD)δ 8.00-7.95 (m, 2H), 7.61-7.56 (m, 2H), 2.64 (s, 1H), 1.54 (s, 6H).

Preparation of 4-(Diethylcarbamoyl)-3-fluoro-benzoic acid

To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) atroom temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol)followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g,5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. Thereaction mixture was diluted with EtOAc and washed with brine solution.The organics were separated, dried and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using EtOAc-DCM(10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0g, 75%). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H),7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24(td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heatedat 65° C. for 2.5 hours. The reaction mixture was cooled, diluted withEtOAc and washed with 2 M HCl solution. The organics were separated,dried and concentrated in vacuo to give4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid.ESI-MS m/z calc. 239.24. found 240.2 (M+1)⁺; Retention time: 0.99minutes (3 min run).

Preparation of 5-Tert-butoxypyridine-2-carboxylic acid

To NaO^(t)Bu (1.57 g, 16.4 mmol) in HMPA (6 mL) was added DMF (6 mL),followed by 5-fluoropyridine-2-carbonitrile (1 g, 8.19 mmol) and thereaction mixture was stirred for 16 hours under an atmosphere ofnitrogen. The reaction mixture was diluted with water (100 mL) andextracted with DCM (3×50 mL) and layers were separated. The organicswere washed sequentially with water (50 mL) and sat. aq. NaHCO₃ solution(50 mL) and the organic layer was separated, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-50% EtOAc/hexanes to give5-tert-butoxypyridine-2-carbonitrile (0.90 g, 62%) as a yellow solid.ESI-MS m/z calc. 176.0. found 177.5 (M+1)⁺; Retention time: 1.3 minutes(3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (dd, J=2.7, 0.5 Hz, 1H),7.67-7.56 (m, 1H), 7.41-7.31 (m, 1H), 1.52-1.38 (m, 10H). To5-tert-butoxypyridine-2-carbonitrile (0.75 g, 4.26 mmol) in ethanol (10mL) was added NaOH (4.3 mL of 5 M, 21.3 mmol) and the reaction mixturewas heated at 85° C. for 1 hour. The reaction mixture was cooled,concentrated in vacuo and diluted with ethyl acetate (50 mL). Theorganic layer was washed with mixture of brine solution (10 mL) and 6NHCl (3 mL). The organic layer was separated, dried over MgSO₄ andconcentrated in vacuo to give 5-tert-butoxypyridine-2-carboxylic acid(0.82 g, 99%) as a yellow solid. ESI-MS m/z calc. 195.1. found 196.1(M+1)⁺; Retention time: 0.62 minutes (3 min run).

Preparation of 3-Fluoro-4-(2-hydroxy-2-methyl-propyl)benzoic acid

Step 1:

Trimethylsilyl diazomethane (11.6 mL of 2 M in toluene, 23.2 mmol) wasadded dropwise to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid(4.5 g, 19.3 mmol) in a mixture of toluene (7.65 mL)/methanol (7.65 mL)under a nitrogen atmosphere at room temperature. The reaction mixturewas then quenched with a few drops of acetic acid and the solvents wereconcentrated in vacuo. The residue was purified by silica gel columnchromatography using 0-10% EtOAc-hexanes as eluent to yield methyl2-(4-bromo-2-fluoro-phenyl)acetate (4.3 g, 91%). ¹H NMR (400 MHz, CDCl₃)δ 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.63 (d,J=1.0 Hz, 2H).

Step 2:

A solution of methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.0 g, 16.2mmol) in THF (56 mL) was cooled to 0° C. under a nitrogen atmosphere andto this solution was added methylmagnesium bromide solution (16.2 mL of3 M in diethyl ether, 48.6 mmol) over 30 minutes. The reaction mixturewas stirred for 2 hours, then quenched with saturated aqueous ammoniumchloride solution and extracted with EtOAc. The aqueous layer wasextracted once more with EtOAc, and the combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography using 0-15%EtOAc-hexanes as eluent to yield1-(4-bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (3.0 g, 75%) as acolorless oil. ESI-MS m/z calc. 246.0. found 231.1 (M-17)⁺; Retentiontime: 1.53 minutes (3 min run); ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.21 (m,2H), 7.14 (t, J=8.1 Hz, 1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz,6H).

Step 3:

A reaction vessel charged with1-(4-bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g, 9.51 mmol),palladium acetate (214 mg, 0.95 mmol),3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.95 mmol) andtriethylamine (4.24 mL, 30.4 mmol) in DMF (26 mL) was added MeOH (20mL). The reaction vessel was charged to 50 psi with CO gas and heated at80° C. for 15 hours. The reaction mixture was allowed to cool,partitioned between EtOAc and brine solution. The layers were separatedand the aqueous layer was extracted once more with EtOAc. The combinedorganics were washed with brine (2×10 mL), dried over Na₂SO₄, filteredand concentrated in vacuo to an orange oil. The residue was purified bysilica gel column chromatography using 0-30% EtOAc-hexanes as eluent toyield methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.83 g,85%). ESI-MS m/z calc. 226.1. found 227.5 (M+1)⁺; Retention time: 1.29minutes (3 min run); ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, J=7.9, 1.7 Hz,1H), 7.71 (dd, J=10.3, 1.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 3.92 (s,3H), 2.88 (d, J=1.3 Hz, 2H), 1.26 (s, 6H).

Step 4:

Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.59 g, 7.03mmol) was dissolved in a mixture of THF (40 mL)/water (20 mL)/MeOH (20mL) and LiOH (1.01 g, 42.2 mmol) was added. The reaction mixture washeated at 55° C. for 30 minutes. The reaction mixture was cooled to roomtemperature and the concentrated in vacuo. The residue was dissolved inwater and cooled to 0° C. and treated with 1 M HCl solution (to pH 3).The resulting precipitate was filtered, washed with water and driedunder high vacuum to yield 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoicacid (999 mg, 67%) as a white solid. ESI-MS m/z calc. 212.1. found 211.1(M−1)⁺; Retention time: 0.98 minutes (3 min run); ¹H NMR (400 MHz,CDCl₃) δ 7.84 (dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=10.1, 1.6 Hz, 1H),7.39 (d, J=15.1 Hz, 1H), 2.91 (s, 2H), 1.28 (s, 6H).

Preparation of 4-(2-Hydroxyethoxy)-3-methyl-benzoic acid

Step 1:

To a solution of methyl 4-hydroxy-3-methyl-benzoate (5.77 g, 34.7 mmol)in DMF (17 mL) was added 2-bromoethanol (6.51 g, 3.7 mL, 52.1 mmol) andcesium carbonate (33.95 g, 104.2 mmol) and the reaction mixture washeated at 60° C. for 16 hours. The reaction mixture was cooled to roomtemperature and then pardoned between water (250 mL) and ethyl acetate(2×100 ml). The organic layers were combined, dried over Na₂SO₄,filtered and concentrated in vacuo to yield a crude oil that waspurified by silica gel column chromatography using EtOAc/hexanes (10 to100%) as eluent to give methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate(1.87 g, 26%) as a white solid. ESI-MS m/z calc. 210.1. found 211.1(M+1)⁺; Retention time: 1.08 minutes (3 min run); ¹H NMR (400 MHz,CDCl₃) δ 7.94-7.79 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 4.23-4.08 (m, 2H),4.08-3.96 (m, 2H), 3.88 (s, 3H), 2.34-2.18 (m, 3H).

Step 2:

To a solution of methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate (1.87 g,8.9 mmol) in dioxane (16 mL) was added 1N NaOH (5 mL) and the reactionmixture was heated at 70° C. for 18 hours. 5M NaOH (0.5 ml) was addedand the reaction was stirred at 70° C. for 22 hours. The reactionmixture was cooled and solvent was concentrated in vacuo and the cruderesidue was dissolved in water (20 mL) and extracted with ethyl acetate(2×20 mL). The aqueous layer was acidified with 1 M HCl solution andextracted with ethyl acetate (2×20 mL). The organics were separated,dried with Na₂SO₄ and concentrated in vacuo to give4-(2-hydroxyethoxy)-3-methyl-benzoic acid (0.77 g, 44%) as a whitesolid. ESI-MS m/z calc. 196.1. found 197.0 (M+1)⁺; Retention time: 0.72minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.96-7.49(m, 2H), 7.00 (d, J=8.6 Hz, 1H), 4.87 (t, J=5.4 Hz, 1H), 4.06 (t, J=5.0Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 2.17 (d, J=20.3 Hz, 3H).

Preparation of 4-Pyrrolidin-1-ylsulfonylbenzoic acid

To a solution of 4-chlorosulfonylbenzoic acid (2 g, 9.07 mmol) indichloromethane (10 mL) was added a solution of pyrrolidine (1.29 g,1.51 mL, 18.1 mmol) in dichloromethane (10 mL) and the reaction mixturewas stirred at room temperature for 24 hours. The reaction mixture wasfiltered and the white solid obtained was washed with water (50 ml) anddiethyl ether (10 ml) and dried under vacuum to give4-pyrrolidin-1-ylsulfonylbenzoic acid (700 mg, 30%). ESI-MS m/z calc.255.0. found 256.3 (M+1)⁺; Retention time: 1.18 minutes (3 min run); ¹HNMR (400 MHz, DMSO) δ 13.49 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.92 (d,J=8.5 Hz, 2H), 3.17 (t, J=6.7 Hz, 4H), 1.65 (t, J=6.7 Hz, 4H).

Preparation of 3-Fluoro-4-(3-methoxyprop-1-ynyl)benzoic acid

Step 1:

To a mixture of methyl 4-bromo-3-fluoro-benzoate (2.5 g, 10.7 mmol) andcopper (I) iodide (204 mg, 1.07 mmol) and palladiumdichlorobis(triphenylphosphine) complex (753 mg, 1.07 mmol) under anatmosphere of argon was added DMF (21 mL) and the reaction mixture wascooled to 0° C. Triethylamine (1.95 mL, 13.9 mmol) was added followed by3-methoxyprop-1-yne (997 μL, 11.8 mmol) and the reaction mixture wasstirred at 60° C. for 70 minutes. The reaction mixture was cooled,diluted with EtOAc and filtered over Celite®. The filtrate was washedsequentially with 1 M HCl, 10% NH₄OH and brine. The organic layer wasseparated, dried and concentrated in vacuo and the resulting residue waspurified by silica gel column chromatography using EtOAc-hexanes(10-100%) as eluent to give methyl3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.45 g, 61%). ESI-MS m/zcalc. 222.2. found 223.2 (M+1)⁺; Retention time: 1.53 minutes (3 minrun); ¹H NMR (400 MHz, CDCl₃) δ 7.75 (ddd, J=11.2, 8.8, 1.5 Hz, 2H),7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).

Step 2:

To methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.4 g, 6.3 mmol) in2:1 mixture of THF:MeOH (15 mL) at room temperature was added 4 M sodiumhydroxide solution (1.9 mL, 7.56 mmol) and reaction mixture was stirredfor 1 hour. The solvent was removed in vacuo and the reaction mixturewas extracted with ethyl ether, and layers were separated. The aqueouslayer was acidified with 1M HCl solution and extracted with ethyl ether.The organics were separated, dried and concentrated in vacuo to give4-(3-hydroxypropoxy)-3-methyl-benzoic acid (1.1 g, 85%) as a whitesolid. ESI-MS m/z calc. 208.2. found 209.2 (M+1)⁺; Retention time: 1.22minutes (3 min run); ¹H NMR (400 MHz, CDCl₃) δ 7.85 (dd, J=8.0, 1.4 Hz,1H), 7.80 (dd, J=9.5, 1.3 Hz, 1H), 7.59-7.49 (m, 1H), 4.39 (s, 2H), 3.48(s, 3H).

Preparation of 4-(3-Hydroxyoxetan-3-yl)benzoic acid

To 4-bromobenzoic acid (434 mg, 2.16 mmol) in THF (9 mL) at −78° C. wasadded dropwise n-butyllithium (2.84 mL of 1.6 M in hexanes, 4.54 mmol).The reaction mixture was stirred for 30 minutes, then oxetan-3-one (218mg, 3.03 mmol) in THF (1 mL) was added dropwise. The reaction mixturewas stirred for 30 minutes at −78° C. and allowed to warm to roomtemperature over 30 minutes. The reaction mixture was diluted with ethylacetate (15 mL) and acidified to pH 2 with 2 N HCl. The layers wereseparated and the aqueous was re-extracted with ethyl acetate (15 mL).The combined organics were washed with brine solution (10 mL), driedover MgSO₄ and concentrated in vacuo to give a white solid as a 1:1mixture of 4-(3-hydroxyoxetan-3-yl)benzoic acid/benzoic acid (380 mg,91%).

Preparation of 4-Tetrahydrofuran-3-ylsulfonylbenzoic acid

Step 1:

To a suspension of methyl 4-sulfanylbenzoate (0.85 g, 5.05 mmol),potassium carbonate (1.39 g, 10.1 mmol) in DMF (10 mL) at roomtemperature was added 3-iodotetrahydrofuran (1.00 g, 5.05 mmol). Theresulting suspension was stirred for 16 hours. The reaction mixture wasdiluted with DCM (25 mL), filtered and the solvent was evaporated underreduced pressure. The residue was dissolved in DCM (25 mL) and washedwith water (3×15 mL) and saturated aqueous brine solution (1×15 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.03 g,86%) as a yellow solid. ESI-MS m/z calc. 238.1. found 239.3 (M+1)⁺;Retention time: 1.47 minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ7.91-7.83 (m, 2H), 7.48-7.39 (m, 2H), 4.16-4.08 (m, 2H), 3.91-3.72 (m,5H), 3.55 (q, J=7.6 Hz, 1H), 2.49-2.35 (m, 1H), 1.86-1.74 (m, 1H).

Step 2:

Methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.01 g, 4.24 mmol) wasdissolved in methanol (25 mL), followed by the addition of water (2.5mL), and Oxone (2.61 g, 4.24 mmol). The reaction mixture was stirred atroom temperature for 24 hours. An additional 0.1 eq of Oxone (0.26 g)was added and the reaction mixture was stirred for 2 hours, thenfiltered and the solvent was concentrated in vacuo. The resultingresidue was dissolved in dichloromethane (30 mL) and washed with water(2×25 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to yield methyl4-tetrahydrofuran-3-ylsulfonylbenzoate (1.07 g, 93%) as a yellow solid.ESI-MS m/z calc. 270.1. found 271.3 (M+1)⁺; Retention time: 1.02 minutes(3 min run).

Step 3:

To methyl 4-tetrahydrofuran-3-ylsulfonylbenzoate (1.07 g, 3.96 mmol) indioxane (11 mL) was added 1 M sodium hydroxide (10.5 mL, 10.5 mmol) andthe reaction was heated at 80° C. for 10 minutes. The solvent wasevaporated under reduced pressure. The residue was dissolved in water(30 mL) and washed with ethyl acetate (3×25 mL). The aqueous layer wasacidified with hydrochloric acid. The aqueous layer was extracted withethyl acetate (2×30 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to yield4-tetrahydrofuran-3-ylsulfonylbenzoic acid (0.86 g, 85%) as a whitesolid. ESI-MS m/z calc. 256.0. found 257.3 (M+1)+; Retention time: 0.69minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 8.19 (d,J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 4.38-4.15 (m, 1H), 4.06-3.97 (m,1H), 3.87-3.71 (m, 2H), 3.72-3.54 (m, 1H), 2.20-2.06 (m, 2H).

Preparation of 3-Methyl-4-methylsulfonyl-benzoic acid

Step 1:

Thionyl chloride (5.8 g, 3.5 mL, 48.7 mmol) was added dropwise to asolution of 4-fluoro-3-methyl-benzoic acid (5.0 g, 32.4 mmol) inmethanol (40 mL). The reaction mixture was stirred at 35° C. for 16hours. The reaction mixture was concentrated in vacuo and the resultingmethyl 4-fluoro-3-methylbenzoate was used in the next step withoutfurther purification. ESI-MS m/z calc. 167.1. found 168.2 (M+1)⁺;Retention time: 1.57 minutes (3 min run). The crude ester was dissolvedin DMF (20 mL) and powdered sodium thiomethoxide (2.3 g, 32.4 mmol) wasadded and the reaction mixture was stirred at room temperature for 1hour and at 80° C. for 1 hour. The reaction mixture was concentrated invacuo, the residue was partitioned between 1M HCl solution and ethylacetate. The layers were separated and the organic was washed with 1Mhydrochloric acid solution. The ethyl acetate layer was then dried overmagnesium sulfate, filtered, and concentrated in vacuo to give methyl3-methyl-4-(methylthio)benzoate. ESI-MS m/z calc. 182.2. found 183.1(M+1)⁺; Retention time: 1.48 minutes (3 min run). Methyl3-methyl-4-(methylthio)benzoate (32.4 mmol) was heated in a mixture ofacetic acid (80 mL) and hydrogen peroxide (40 mL of 30% w/w,) at 80° C.for 30 minutes. The reaction mixture was cooled, concentrated in vacuoand then partitioned between water and ethyl acetate. The layers wereseparated and the organic was washed sequentially with water (1×20 mL),sat. NaHCO₃ (1×20 mL) and brine (1×20 mL), then dried over MgSO₄ andconcentrated in vacuo. The residue was triturated with ethyl ether togive methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g) as a white solid.The mother liquor was concentrated in vacuo then triturated with hexanes(3×) to give a second crop (1.2 g) (combined yield 95%). ESI-MS m/zcalc. 228.3. found 229.5 (M+1)⁺; Retention time: 1.04 minutes (3 minrun); ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.09 (m, 1H), 8.04-8.00 (m, 2H),3.96 (s, 3H), 3.10 (s, 3H), 2.77 (s, 3H).

Step 2:

To a mixture of methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g, 25.4mmol) in dioxane (25 mL) was added NaOH (20 g, 125.0 mmol) (aq. 25%) andthe reaction mixture was heated at 75° C. for 1 hour. The reactionmixture was cooled and was concentrated in vacuo to half the volume andadjusted to pH 2 with 6N HCl solution. The aqueous layer was extractedwith ethyl acetate (3×100 mL). The organics were washed with brinesolution (50 mL), dried over MgSO₄ and concentrated in vacuo to give3-methyl-4-methylsulfonyl-benzoic acid (5.3 g, 97%) as a white solid.ESI-MS m/z calc. 214.5. found 215.5 (M+1)⁺; Retention time: 0.67 minutes(3 min run); ¹H NMR (400 MHz, DMSO) δ 13.48 (s, 1H), 8.13-7.81 (m, 3H),3.33 (s, 3H), 2.70 (s, 3H).

Preparation of 4-Ethoxy-3-(hydroxymethyl)benzoic acid

Step 1:

A suspension of methyl 3-formyl-4-hydroxy-benzoate (3.0 g, 16.7 mmol),bromoethane (2.7 g, 1.85 mL, 24.9 mmol) and powdered K₂CO₃ (6.9 g, 49.9mmol) in DMF (15 mL) was heated at 40° C. for 16 hours. After 16 hours,a further aliquot of bromoethane (1 mL) was added and the reactionmixture was heated for a further 2 hours. The reaction mixture wasdiluted with DCM (50 mL), filtered and concentrated in vacuo to give ayellow solid, which was diluted with ether (200 mL), washed sequentiallywith water (50 mL), sat. aq. NaHCO₃ (50 mL) and brine solution (50 mL).The organics were separated, dried over MgSO₄ and concentrated in vacuoto give methyl 4-ethoxy-3-formylbenzoate (3.52 g, 100%) as a whitesolid. ESI-MS m/z calc. 208.0. found 209.3 (M+1)⁺; Retention time: 1.34minutes (3 min run). Methyl 4-ethoxy-3-formylbenzoate (1.73 g, 8.91mmol) was dissolved in THF (20 mL) and cooled to 0° C. LiBH₄ (100 mg,4.59 mmol) was added and the reaction mixture was stirred for 1 hour,then slowly quenched with dropwise addition of acetic acid. The reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL),washed sequentially with sat. aq. NaHCO₃ (20 mL) and brine (20 mL). Theorganics were separated, dried over MgSO₄ and purified by silica gelcolumn chromatography using 0-100% EtOAc/DCM as eluent to give methyl4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 46%) as a white solid. ESI-MSm/z calc. 210.0. found 211.3 (M+1)⁺; Retention time: 1.11 minutes (3 minrun); ¹H NMR (400 MHz, CDCl₃) δ 8.05-7.86 (m, 2H), 6.99-6.79 (m, 1H),4.72 (s, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 1.64 (d, J=7.0 Hz,2H), 1.47 (t, J=7.0 Hz, 3H).

Step 2:

To a solution of methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 7.61mmol) in dioxane (10 mL) was added NaOH (6.0 g, 37.5 mmol) and thereaction mixture was heated at 50° C. for 2 hours. The reaction mixturewas concentrated in vacuo to half-volume, acidified to pH 2 with aq. 6NHCl solution. The resulting suspension was filtered, the solid rinsedwith water and acetonitrile, then dried in vacuo to give4-ethoxy-3-(hydroxymethyl)benzoic acid (740 mg, 50%) as a white solid.¹H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.00 (s, 1H), 7.81 (dd, J=8.5,2.2 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 5.13 (t, J=5.7 Hz, 1H), 4.50 (d,J=5.2 Hz, 2H), 4.11 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H).

Preparation of 2-Methyl-4-methylsulfonyl-benzoic acid

Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL).The reaction mixture was stirred at 60° C. for 2 hours. The reactionmixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoatewas used in the next step without further purification. Methyl4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodiumthiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture washeated to 80° C. for 2 hours. The reaction mixture was then partitionedbetween 1M hydrochloric acid and ethyl acetate. The layers wereseparated and the organic layer was washed with 1M hydrochloric acid,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 2-methyl-4-(methylthio)benzoic acid which was carried to the nextstep without further purification. 2-Methyl-4-(methylthio)benzoic acidwas suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30%w/w) was added and the reaction mixture was heated to 80° C. for 2hours. The reaction mixture was concentrated in vacuo, then partitionedbetween 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers wereseparated and the aqueous extracted with ethyl acetate (50 mL). Thecombined organics washed with brine (20 mL), dried over MgSO₄ andconcentrated in vacuo. The resulting solid was rinsed with ether (2×10mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid(0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. found 215.5(M+1)⁺; Retention time: 0.48 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s,3H), 2.59 (s, 3H).

Preparation of 3-Methoxy-4-methylsulfonyl-benzoic acid

To 3-fluoro-4-methylsulfonyl-benzoic acid (490 mg, 2.25 mmol), sodiumhydride (270 mg, 6.74 mmol), methanol (1.55 g, 2.0 mL, 48.3 mmol) wasadded DMF (5 mL) and reaction mixture was heated at 100° C. for 1 hour.The reaction mixture was cooled and diluted with EtOAc and acidifiedusing 1 M HCl solution. The organic layer was separated, washed withsaturated aqueous brine solution (3×), dried over sodium sulfate andconcentrated in vacuo to give 3-methoxy-4-methylsulfonyl-benzoic acid(496 mg, 95%). ESI-MS m/z calc. 230.0. found 231.3 (M+1)⁺; Retentiontime: 0.49 minutes (3 min run).

Preparation of 4-[Cyclopropyl(hydroxy)methyl]benzoic acid

Step 1:

(4-Ethoxycarbonylphenyl)-iodo-zinc (20 mL of 0.5 M in THF, 10.0 mmol)was added over 10 min to dichloro-bis(triphenylphosphoranyl)palladium(211 mg, 0.3 mmol) in THF (20 mL) under an atmosphere of nitrogen at 0°C. The reaction mixture was stirred for 15 minutes, cyclopropanecarbonylchloride (941 mg, 817 μL, 9.0 mmol) was added dropwise at 0° C. andstirred for 2 hours. The reaction mixture was quenched with 1M HCl (20mL), extracted with ethyl acetate (2×50 mL). The organic layer waswashed sequentially with sat. aq. NaHCO₃ (5 mL) and brine solution (50mL), dried over MgSO₄ and purified by silica gel column chromatographyusing 0-30% EtOAc/hexanes as eluent to give ethyl4-(cyclopropanecarbonyl)benzoate (1.54 g, 71%) as a pale yellow oil.ESI-MS m/z calc. 218.0. found 219.3 (M+1)⁺; Retention time: 1.57 minutes(3 min run).

Step 2:

To ethyl 4-(cyclopropanecarbonyl)benzoate (400 mg, 1.83 mmol) in ethanol(10 mL) was added at room temperature NaBH₄ (69 mg, 1.83 mmol) and thereaction mixture was stirred for 1 hour. The reaction mixture was thenconcentrated in vacuo and NaOH (1.5 g, 9.38 mmol) and dioxane (1.5 mL)were added and the reaction mixture was heated at 80° C. for 3 hours.The reaction mixture was concentrated in vacuo to half the volume and pHwas adjusted to 2 with 3 N HCl. The aqueous layer was extracted withethyl acetate (3×10 mL), and the combined organics were washed withbrine solution (5 mL), dried over MgSO₄ and concentrated in vacuo togive 4-[cyclopropyl(hydroxy)methyl]benzoic acid (300 mg, 85%). ESI-MSm/z calc. 192.2. found 193.5 (M+1)⁺; Retention time: 0.78 minutes (3 minrun); ¹H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 5.33 (d, J=4.4 Hz, 1H), 4.04 (dd, J=7.3, 4.3 Hz, 1H), 1.12-0.87(m, 1H), 0.54-0.20 (m, 4H).

Preparation of 3-Fluoro-4-isopropoxy-benzoic acid

Step 1:

To methyl 3-fluoro-4-hydroxy-benzoate (2.0 g, 11.8 mmol) in DMF (12 mL)was added K₂CO₃ (6.50 g, 47.04 mmol) followed by 2-iodopropane (2.35 mL,23.5 mmol). The reaction mixture was heated at 60° C. for 1.5 hours. Thereaction mixture was cooled and diluted with EtOAc, filtered and thesolvent was evaporated in vacuo. The resulting residue was dissolved inEtOAc and washed sequentially with water (3×10 mL) and brine solution(1×10 mL). The organics were separated and dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired ester. ESI-MS m/z calc.212.2. found 213.3 (M+1)⁺; Retention time: 1.7 minutes (3 min run). ¹HNMR (400 MHz, DMSO) δ 7.76 (ddd, J=8.6, 2.1, 1.2 Hz, 1H), 7.69 (dd,J=11.9, 2.1 Hz, 1H), 7.31 (t, J=8.6 Hz, 1H), 4.79 (dt, J=12.1, 6.0 Hz,1H), 3.82 (s, 3H), 1.32 (d, J=6.5 Hz, 6H).

Step 2:

To the ester from above was added dioxane (31 mL) and NaOH solution(31.2 mL of 1 M, 31.2 mmol) and the reaction was heated at 80° C. for 20minutes, then concentrated in vacuo. The crude mixture was dissolved inwater and washed with EtOAc (3×10 mL). The layers were separated and theaqueous layer was acidified using 1 M HCl solution. The aqueous layerwas extracted with EtOAc (3×10 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to yield3-fluoro-4-isopropoxy-benzoic acid (1.7 g, 72%) as a white solid. ESI-MSm/z calc. 198.1. found 199.1 (M+1)⁺; Retention time: 1.7 minutes (3 minrun). ¹H NMR (400 MHz, DMSO) δ 12.90 (br s, 1H), 7.73 (ddd, J=8.6, 2.0,1.1 Hz, 1H), 7.65 (dd, J=11.9, 2.1 Hz, 1H), 7.28 (t, J=8.6 Hz, 1H), 4.77(hept, J=6.1 Hz, 1H), 1.32 (d, J=6.0 Hz, 6H).

Preparation of 4-Isopropoxy-3-methoxy-benzoic acid

Step 1:

2-Bromopropane (3.39 mL, 36.2 mmol) was added to a suspension of4-bromo-2-methoxy-phenol (5 g, 24.1 mmol), K₂CO₃ (6.67 g, 48.3 mmol) andDMSO (71 mL) at room temperature. The heterogeneous mixture was stirredat 55° C. for 2 hours, then cooled to room temperature and diluted withwater. The reaction mixture was extracted with Et₂O and the extract waswashed successively with 10% aq. NaOH solution, water, then brinesolution. The organics were separated and dried over sodium sulfate,filtered and concentrated in vacuo to give4-bromo-1-isopropoxy-2-methoxy-benzene (5.83 g, 94%) as a pale yellowoil. ESI-MS m/z calc. 244.0. found 245.0 (M+1)⁺; Retention time: 1.93minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.03-6.95 (m, 2H), 6.76(dd, J=7.7, 1.1 Hz, 1H), 4.47 (dt, J=12.2, 6.1 Hz, 1H), 3.84 (s, 3H),1.35 (d, J=6.1 Hz, 6H).

Step 2:

Under an atmosphere of nitrogen, tert-butyllithium (2.14 mL of 1.6 M intoluene, 3.42 mmol) was added dropwise to a solution of4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6 mL)at −78° C. The reaction mixture was allowed to stir for 1 hour at −78°C., then added dropwise to a flask containing CO₂ (1.8 g, 40.8 mmol)(solid, dry ice) in THF (2 mL). The reaction mixture was allowed to stirfor 30 minutes warming to room temperature. Water (20 mL) was added tothe reaction mixture and the volatiles were removed in vacuo. Theresultant aqueous layer was acidified with 1N HCl solution to pH 1 andwas extracted with ethyl acetate (3×15 mL). The organics were separatedand the combined organics were washed with brine solution, dried oversodium sulfate, filtered and concentrated in vacuo to give4-isopropoxy-3-methoxy-benzoic acid (310 mg, 85%) as a white solid.ESI-MS m/z calc. 210.1. found 211.1 (M+1)⁺; Retention time: 1.23 minutes(3 min run). ¹H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4,2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt,J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).

Preparation of 4-Isobutylsulfonylbenzoic acid

Step 1:

Potassium carbonate (1.2 g, 8.9 mmol) was added to a mixture of methyl4-sulfanylbenzoate (1.0 g, 6.0 mmol), 1-bromo-2-methyl-propane (1.2 g,970 μL, 8.9 mmol), and DMF (10 mL) at room temperature. The reactionmixture was allowed to stir for 4 hours and the resulting solid wasremoved by filtration. The filtrate were partitioned between ethylacetate (100 mL) and water (100 mL). The layers were separated and theorganic layer was washed with brine solution, then dried over sodiumsulfate, filtered and concentrated in vacuo to give methyl4-isobutylsulfanylbenzoate (1.1 g, 83%) as a clear oil. ESI-MS m/z calc.242.0. found 243.2 (M+1)⁺; Retention time: 1.73 minutes (3 min run). ¹HNMR (400 MHz, CDCl₃) δ 8.30 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H),3.03 (d, J=6.5 Hz, 2H), 2.27 (dt, J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7Hz, 6H).

Step 2:

3-Chlorobenzenecarboperoxoic acid (3.6 g, 15.6 mmol) was added to asolution of methyl 4-isobutylsulfanylbenzoate (1.0 g, 4.5 mmol) in DCM(20 mL) at room temperature. The reaction mixture was allowed to stirfor 2 hours, then concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography using (0-100%) ethylacetate/hexanes as eluent to give methyl 4-isobutylsulfonylbenzoate.ESI-MS m/z calc. 256.1. found 257.2 (M+1)⁺; Retention time: 1.96 minutes(3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.4 Hz, 2H), 8.00 (d,J=8.3 Hz, 2H), 3.98 (s, 3H), 3.02 (d, J=6.5 Hz, 2H), 2.25 (dp, J=13.3,6.6 Hz, 1H), 1.07 (d, J=6.7 Hz, 6H).

Step 3:

A mixture of methyl 4-isobutylsulfonylbenzoate (1.0 g, 3.9 mmol), NaOHsolution (10 mL of 1 M, 10.00 mmol), and dioxane (10 mL) was heated at80° C. for 1.5 hours. The reaction mixture was cooled to roomtemperature, then concentrated in vacuo. The solid residue was dissolvedin water and washed with ethyl acetate (1×10 mL). The aqueous layer wasacidified with 1N HCl solution and was extracted with ethyl acetate(2×10 mL) and layers were separated. The combined organics were washedwith brine, dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using (0-100%)ethyl acetate/hexanes as eluent to give 4-isobutylsulfonylbenzoic acid(1.0 g, 98%). ESI-MS m/z calc. 242.1. found 243.2 (M+1)⁺; Retentiontime: 1.73 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=8.3Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 3.03 (d, J=6.5 Hz, 2H), 2.27 (dt,J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7 Hz, 6H).

Preparation of 4-(2-Hydroxy-2-methyl-propoxy)benzoic acid

Step 1:

A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL),4-hydroxybenzonitrile (2 g, 16.8 mmol), K₂CO₃ (9.3 g, 67.3 mmol) inwater (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. Thereaction mixture was cooled and the solvent was concentrated in vacuo.The residue was diluted with ether (200 mL) and filtered and thefiltrate was washed sequentially with water (50 mL) and brine solution(50 mL). The organics were separated and dried over MgSO₄ and solventwas removed in vacuo to give a residue which was purified by silica gelcolumn chromatography using (0-100%) EtOAc/DCM as eluent to give4-(2-hydroxy-2-methyl-propoxy)benzonitrile (3.0 g, 94%) as a yellowsolid. ESI-MS m/z calc. 191.1. found 192.3 (M+1)⁺; Retention time: 1.05minutes (3 min run).

Step 2:

To 4-(2-hydroxy-2-methyl-propoxy)benzonitrile (1.0 g, 5.2 mmol) inethanol (15 mL) was added NaOH solution (5 mL of 5 M, 25 mmol) and thereaction mixture was heated at 85° C. for 1 hour, concentrated in vacuoand diluted with ethyl acetate (50 mL). To the organic layer was added amixture of brine solution (10 mL) and 6N HCl (3 mL, to adjust to pH 6).The organic layer was separated, dried over MgSO₄ and concentrated invacuo to give a yellow solid, which was triturated twice with diethylether to give 4-(2-hydroxy-2-methyl-propoxy)benzoic acid (0.8 g, 76%) asa white solid. ESI-MS m/z calc. 195.1. found 196.1 (M+1)⁺; Retentiontime: 0.62 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ 12.59 (s, 1H),7.98-7.66 (m, 2H), 7.09-6.81 (m, 2H), 4.66 (d, J=9.3 Hz, 1H), 3.77 (d,J=7.9 Hz, 2H), 1.30-1.00 (s, 6H).

Preparation of 3-(Hydroxymethyl)-4-isopropoxy-benzoic acid

Step 1:

To a mixture of methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol),potassium carbonate (30.7 g, 222.0 mmol) and N,N-dimethylformamide (62.5mL) was added 2-iodopropane (18.9 g, 11.1 mL, 111.0 mmol) and thereaction mixture was heated at 60° C. for 18 hours. The reaction mixturewas filtered, the filtrate was concentrated in vacuo to give a residuewhich was dissolved in ethyl acetate (150 mL) and washed sequentiallywith water (3×75 mL) and brine solution (1×75 mL). The layers wereseparated and the organic layer was dried over sodium sulfate, filteredand concentrated in vacuo to yield methyl 3-formyl-4-isopropoxy-benzoate(12.2 g, 99%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. found223.3 (M+1)⁺; Retention time: 1.51 minutes (3 min run). ¹H NMR (400 MHz,DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz,1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d,J=6.0 Hz, 6H).

Step 2:

Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.8 mmol) was dissolvedin tetrahydrofuran (5 mL) and lithium borohydride (35 mg, 1.6 mmol) wasadded. The reaction mixture was stirred at room temperature for 30minutes, then quenched with methanol (3 mL). The reaction mixture wasneutralized by the addition of a saturated aqueous solution of sodiumbicarbonate (3 mL) and extracted with ethyl acetate (3×10 mL). Theorganic layers were washed with brine solution (1×10 mL), dried oversodium sulfate, filtered and concentrated in vacuo to yield methyl3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 99%) as a viscousliquid. ESI-MS m/z calc. 224.3. found 225.3 (M+1)⁺; Retention time: 1.26minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.89 (d,J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.86-4.68(m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 1.35 (d, J=6.0 Hz, 6H).

Step 3:

To methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 0.8 mmol) indioxane (2 mL) was added sodium hydroxide (2.1 mL of 1 M, 2.1 mmol) andthe reaction mixture was heated at 80° C. for 50 minutes. The solventwas evaporated under reduced pressure. The residue was dissolved inwater (10 mL) and washed with ethyl acetate (3×10 mL). The layers wereseparated and aqueous layer was acidified with hydrochloric acid. Theaqueous layer was extracted with ethyl acetate (3×10 mL). The organiclayer was separated, dried over sodium sulfate, filtered andconcentrated in vacuo to yield 3-(hydroxymethyl)-4-isopropoxy-benzoicacid (150 mg, 89%) as a white solid. ESI-MS m/z calc. 210.2. found 211.3(M+1)⁺; Retention time: 1.01 minutes (3 min run).

Preparation of 3-Methoxy-4-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)benzoicacid

Step 1:

To MgSO₄ (4.8 g, 1.8 mL, 40 mmol) in DCM (40 mL) was added H₂SO₄ (1.0 g,533 μL, 10 mmol) at 0° C. and the reaction mixture was allowed to stirfor 30 minutes. 4-Bromo-3-methoxy-benzoic acid (2.3 g, 10 mmol) wasadded followed by 2-methylpropan-2-ol (3.7 g, 4.8 mL, 50 mmol). Thereaction mixture was allowed to stir at room temperature for 16 hours.MgSO₄ was removed by filtration and 1N NaOH solution was added until pH9 was achieved. The layers were separated and the organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo to yieldtert-butyl 4-bromo-3-methoxy-benzoate (0.4 g, 14%).

Step 2:

To difluorozinc (36 mg, 0.35 mmol) and Pd (^(t)Bu₃P)₂ (7 mg, 0.01 mmol)under an atmosphere of nitrogen was added tert-butyl4-bromo-3-methoxy-benzoate (200 mg, 0.69 mmol) dissolved in DMF (2.5mL), followed by (1-methoxy-2-methyl-prop-1-enoxy)-trimethylsilane (182mg, 1.05 mmol). The reaction mixture was heated at 80° C. for 16 hours.The reaction mixture was cooled, filtered and partitioned between EtOAcand brine solution. The organics were separated, dried over sodiumsulfate and concentrated in vacuo. The resulting residue was dissolvedin DCM (1 mL) and treated with TFA (794 mg, 537 μL, 6.97 mmol). Thereaction mixture was allowed to stir for 2 hours and the solvent wasconcentrated in vacuo, the residue was dissolved in DMF, filtered andpurified by HPLC using MeOH:H₂O mixture (1-99%) with HCl modifier (5 mM)to give 3-methoxy-4-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)benzoic acid (55mg, 31%). ESI-MS m/z calc. 252.0. found 253.2 (M+1)⁺; Retention time:2.46 minutes (3 min run).

Preparation of 4-ethoxy-3-methylbenzoic acid

Step 1:

To a solution of 4-hydroxy-3-methyl-benzoic acid (1.00 g, 6.57 mmol) inN,N-dimethylformamide (10 mL) was added potassium carbonate (2.73 g,19.7 mmol) and bromoethane (3.58 g, 2.44 mL, 32.9 mmol). The reactionmixture heated at 45° C. for 48 h in a sealed tube. The reaction mixtureallowed to cool then diluted with water and ether. The ether layer waswashed with 50% saturated NaHCO₃ (50 mL) and brine (50 mL), dried overNa₂SO₄, and concentrated in vacuo to provide ethyl4-ethoxy-3-methylbenzoate as an orange-colored oil. The crude productwas taken directly to the next step. ESI-MS m/z calc. 208.10994. found209.3 (M+1)⁺; Retention time: 1.78 minutes (3 min run).

Step 2:

The crude ethyl 4-ethoxy-3-methyl-benzoate was suspended in a solutionof NaOH (10.5 g, 263 mmol) in water (50 mL) and methanol (25 mL). Thereaction mixture was refluxed for 1 h. The reaction mixture was cooledto 0° C., acidified with 12 M HCl (24.7 mL, 296 mmol) and the resultingsolid filtered. The solid was slurried with acetonitrile and filtered toprovide 4-ethoxy-3-methyl-benzoic acid (760 mg, 4.22 mmol, 64%) as alight pink solid. ESI-MS m/z calc. 180.07864. found 181.3 (M+1)⁺;Retention time: 1.31 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H),7.00 (d, J=8.6 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.17 (s, 3H), 1.36 (t,J=7.0 Hz, 3H).

Preparation of 3-methyl-4-propoxybenzoic acid

Step 1:

To a solution of 4-hydroxy-3-methyl-benzoic acid (3.00 g, 19.7 mmol) inN,N-dimethylformamide (30 mL) was added and 1-iodopropane (16.8 g, 9.62mL, 98.6 mmol). The reaction mixture was stirred at 60° C. for 3 h. Thereaction mixture was allowed to cool then diluted with water and ether.The ether layer was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, and concentrated. Silica gel chromatography (5-30% ethylacetate/hexane) provided propyl 3-methyl-4-propoxybenzoate as anorange-colored oil that was taken directly to the next step.

Step 2:

The crude propyl 3-methyl-4-propoxybenzoate was dissolved in methanol(25 mL) and water (50 mL) and treated with solid sodium hydroxide (31.6g, 789 mmol). The reaction mixture was refluxed for 1 h. The reactionmixture cooled to 0° C. and acidified with 12 M HCl (74 mL, 890 mmol).The resulting solid filtered to provide 3-methyl-4-propoxybenzoic acid(3.22 g, 16.6 mmol, 84%) as a light pink solid. ESI-MS m/z calc.194.0943. found 195.3 (M+1)⁺; Retention time: 1.41 minutes (3 min run).¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H),7.73 (d, J=1.4 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H),2.18 (s, 3H), 1.82-1.69 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).

Preparation of 4-(1-hydroxycyclobutyl)-3-methylbenzoic acid

To a solution of 4-bromo-3-methyl-benzoic acid (2.95 g, 13.7 mmol) intetrahydrofuran (53 mL) at −78° C. was added n-butyllithium (17.6 mL of1.6 M in hexanes, 28 mmol) dropwise while maintaining the internaltemperature below −65° C. resulting in a thin, light yellow slurry. Themixture was stirred at −78° C. for 30 min. Cyclobutanone (962 mg, 1.03mL, 13.7 mmol) was added dropwise to the above slurry while maintainingthe internal temperature below −65° C. The mixture was stirred at −78°C. for 10 min, warmed to room temperature and stirred for 2 h. Thereaction mixture was quenched with saturated NH₄Cl (50 mL) and 1N HCl(25 mL) then extracted with ethyl acetate (3×100 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-10% methanol/dichloromethane) provided theproduct as an off-white solid. The solid was slurried with hexanes,filtered, and dried to provide 4-(1-hydroxycyclobutyl)-3-methyl-benzoicacid (1.30 g, 6.30 mmol, 46%) as a white solid. ESI-MS m/z calc.189.09155. found 189.5 (M-OH)⁺; Retention time: 1.0 minute (3 min run).¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 7.77-7.66 (m, 2H), 7.36 (d,J=7.8 Hz, 1H), 5.38 (s, 1H), 2.56-2.51 (m, 2H), 2.38 (s, 3H), 2.32-2.23(m, 2H), 2.06-1.90 (m, 1H), 1.61-1.51 (m, 1H).

Preparation of 4-(1-hydroxycyclopentyl)-3-methylbenzoic acid

4-Bromo-3-methyl-benzoic acid (4.00 g, 18.6 mmol) was dissolved intetrahydrofuran (80 mL) and the solution was cooled to −78° C.n-Butyllithium (16.4 mL of 2.5 M in hexanes, 40.9 mmol) was addeddropwise over 20 min while maintaining the internal temperature below−65° C. resulting in a thin, light yellow slurry. The reaction mixturewas allowed to stir for 30 min at −78° C. Cyclopentanone (1.57 g, 1.65mL, 18.6 mmol) was then added in a dropwise manner. The mixture wasstirred at −78° C. for 30 min, warmed to room temperature and stirredfor 2 h. The reaction mixture was then diluted with 1 M NaOH (100 mL)and washed with diethyl ether. The organic layer was discarded and theaqueous layer was acidified with 4 M HCl to <pH 3. The aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined extracts were driedover Na₂SO₄ and concentrated in vacuo. The crude product was filteredthrough silica gel eluting with 0-10% methanol/dichloromethane, and allproduct containing fraction concentrated in vacuo. The resulting solidwas slurried in dichloromethane and filtered to provide4-(1-hydroxycyclopentyl)-3-methylbenzoic acid (1.10 g, 26%) as a whitesolid. ESI-MS m/z calc. 220.10994. found 221.5 (M+1)⁺; Retention time:1.16 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ 12.74 (s, 1H),7.70 (d, J=1.4 Hz, 1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.51 (d, J=8.2 Hz,1H), 4.77 (s, 1H), 2.54 (s, 3H), 2.07-1.98 (m, 2H), 1.98-1.89 (m, 2H),1.87-1.77 (m, 2H), 1.72-1.59 (m, 2H).

Preparation of 3-fluoro-4-(1-hydroxycyclopentyl)benzoic acid

4-Bromo-3-fluoro-benzoic acid (3.00 g, 13.7 mmol) was dissolved intetrahydrofuran (60 mL) and the solution was cooled to −78° C.n-Butyllithium (18.8 mL of 1.6 M in hexanes, 30 mmol) was added dropwiseover 20 min while maintaining the internal temperature under −70° C. Thereaction mixture was allowed to stir for 30 min at −78° C. and thencyclopentanone (1.21 mL, 13.7 mmol) was added in a dropwise whilemaintaining the internal temperature below −70° C. The mixture wasstirred at −78° C. for 30 min the allowed to warm to room temperature.The reaction mixture was diluted with saturated NH₄Cl (50 mL) and 1 MHCl (25 mL) and extracted with dichloromethane (3×50 mL). The combinedextracts were dried over Na₂SO₄ and concentrated in vacuo. Silica gelchromatography (0-5% methanol/dichloromethane) provided3-fluoro-4-(1-hydroxycyclopentyl)benzoic acid (400 mg, 13%) as a whitesolid. ESI-MS m/z calc. 224.1. found 225.3 (M+1)⁺; Retention time: 1.16minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s, 1H),7.80-7.70 (m, 2H), 7.60-7.51 (m, 1H), 5.13 (s, 1H), 2.08-1.95 (m, 2H),1.95-1.81 (m, 4H), 1.81-1.67 (m, 2H).

Preparation of 4-(1-hydroxycyclopentyl)benzoic acid

A solution of 4-bromobenzoic acid (4.02 g, 20.0 mmol) in tetrahydrofuran(100 mL) was purged with argon for 5 min. n-Butyllithium (16.0 mL of 2.5M in hexanes, 40 mmol) was added dropwise at −78° C., resulting in ayellow thick syrup. The mixture was stirred at −78° C. for 30 min.Cyclopentanone (3.89 mL, 44.0 mmol) was added dropwise. The reaction wasquenched immediately with saturated NH₄Cl and allowed to warm to roomtemperature. The mixture was acidified with 1 N HCl to pH˜3 andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over MgSo₄ and concentrated in vacuo. The solidresidue was suspended in hexanes, filtered, and the solid washed withadditional hexanes. The solid was re-suspended in dichloromethanefollowed by hexanes. The resulting precipitate was filtered, washed withhexane and air dried to yield 4-(1-hydroxycyclopentyl)benzoic acid (1.25g, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H),7.88 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.93 (s, 1H), 1.93-1.71(m, 8H).

Preparation of 4-(1-hydroxycyclohexyl)benzoic acid

To a solution of 4-bromobenzoic acid (3.00 g, 14.9 mmol) intetrahydrofuran (54 mL) at −78° C. was added n-butyllithium (19.1 mL of1.6 M in hexanes, 30.6 mmol) dropwise while maintaining the internaltemperature below −65° C. The mixture was stirred at −78° C. for 30 min.Cyclohexanone (1.55 mL, 14.9 mmol) was added dropwise while maintainingthe reaction temperature below −65° C. The mixture was stirred at −78°C. for 10 min then allowed to warm to room temperature and stirred for 2h. The reaction mixture was quenched with saturated NH₄Cl (50 mL) and 1NHCl (25 mL). The mixture was extracted with ethyl acetate (3×100 mL).The combined organics were dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was stirred with 1:1 dichloromethane/hexane (20mL) to provide a white solid, which was filtered and discarded. Thefiltrate was concentrated in vacuo and purified by silica gelchromatography (0-5% methanol/dichloromethane) to provide an off-whitesolid. The solid was stirred with hexane, filtered, and dried to provide4-(1-hydroxycyclohexyl)benzoic acid (375 mg, 11%). ESI-MS m/z calc.220.1. found 221.3 (M+1)⁺; Retention time: 1.18 minutes (3 min run). ¹HNMR (400 MHz, DMSO-d₆) δ 12.77 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (d,J=8.5 Hz, 2H), 4.84 (s, 1H), 1.81-1.46 (m, 9H), 1.35-1.17 (m, 1H).

Preparation of 4-(3-hydroxypentan-3-yl)-3-methylbenzoic acid

4-Bromo-3-methyl-benzoic acid (3.00 g, 14.0 mmol) was dissolved intetrahydrofuran (60 mL) and cooled to −78° C. n-Butyllithium (19.2 mL of1.6 M in hexanes, 31 mmol) was added dropwise over 20 min whilemaintaining the internal temperature below −70° C., resulting in theformation of a yellow precipitate. The mixture was stirred for 30 min at−78° C. Pentan-3-one (1.48 mL, 14.0 mmol) was added dropwise whilemaintaining the internal temperature below −70° C. The reaction mixturewas allowed to stir for 30 min at −78° C. then allowed to warm to roomtemperature. The reaction mixture was quenched with saturated NH₄Cl (50mL), stirred for 10 min, then further diluted with 1 N HCl until pH<3.The mixture was then extracted with ethyl acetate (3×100 mL). Thecombined extracts were dried over Na₂SO₄ and concentrated in vacuo.Silica gel chromatography (0-5% methanol/dichloromethane) provided theproduct as an off-white solid, which was slurried in 1:1dichloromethane/hexanes and filtered to provide4-(1-ethyl-1-hydroxy-propyl)-3-methyl-benzoic acid (1.56 g, 50%) as awhite solid. ESI-MS m/z calc. 222.1. found 223.3 (M+1)⁺; Retention time:1.22 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H),7.71-7.64 (m, 2H), 7.58 (d, J=8.1 Hz, 1H), 4.59 (s, 1H), 2.47 (s, 3H),2.02-1.87 (m, 2H), 1.81-1.66 (m, 2H), 0.64 (t, J=7.4 Hz, 6H).

Preparation of 4-(3-hydroxypentan-3-yl)benzoic acid

Step 1:

To a solution of methyl 4-sulfanylbenzoate (2.00 g, 11.9 mmol) inN,N-dimethylformamide (13 mL) was added potassium carbonate (6.57 g,47.6 mmol) and 1-bromo-3-chloro-propane (2.35 mL, 23.8 mmol). Themixture was heated at 60° C. for 16 h. The reaction mixture was filteredand the solvent removed in vacuo. The material was dissolved indichloromethane (10 mL) and washed with water (3×10 mL) and a saturatedaqueous NH₄Cl (10 mL). The organic layer was dried over Na₂SO₄, filteredand the solvent removed in vacuo. Silica gel chromatography (0-100%dichloromethane/hexane) provided methyl4-(3-chloropropylsulfanyl)benzoate (1.87 g, 64%) as a colorless viscousliquid. ESI-MS m/z calc. 244.0. found 245.1 (M+1)⁺; Retention time: 1.83minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz, 2H),7.43 (d, J=8.2 Hz, 2H), 3.84 (s, 3H), 3.79-3.61 (m, 2H), 3.18 (t, J=7.2Hz, 2H), 2.20-1.97 (m, 2H).

Step 2:

Methyl 4-(3-chloropropylsulfanyl)benzoate (1.84 g, 7.52 mmol) wasdissolved in methanol (46 mL), followed by the addition of water (4.6mL) and Oxone (4.62 g, 7.52 mmol). The reaction mixture was stirred atroom temperature for 14 h. The reaction mixture was filtered and thesolvent removed in vacuo. The resulting solid was dissolved indichloromethane and washed with water (2×10 mL). The organic layer wasdried over Na₂SO₄, filtered and the solvent removed in vacuo to yieldmethyl 4-(3-chloropropylsulfonyl)benzoate (1.89 g, 91%) as a viscousliquid. ESI-MS m/z calc. 276.0. found 277.1 (M+1)⁺; Retention time: 1.36minutes (3 min run). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=8.3 Hz, 2H),8.07 (d, J=8.3 Hz, 2H), 3.92 (s, 3H), 3.73-3.46 (m, 4H), 2.21-1.79 (m,2H).

Step 3:

To a solution of methyl 4-(3-chloropropylsulfonyl)benzoate (1.89 g, 6.83mmol) in 2-methylpropan-2-ol (20 mL) was added potassium tert-butoxide(1.53 g, 13.7 mmol) and the slurry heated at 80° C. for 10 min.Additional 2-methylpropan-2-ol (20 mL) was added to facilitate stirringand the heating continued for 25 min. The reaction mixture was dilutedwith water (100 mL) and washed with ethyl acetate (3×100 mL). Theaqueous layer was acidified with 1N HCl and extracted with ethyl acetate(3×100 mL). The combined organics were dried over Na₂SO₄, filtered andthe solvent removed in vacuo to provide 4-cyclopropylsulfonylbenzoicacid (1.22 g, 79%) as a beige solid. ESI-MS m/z calc. 226.0. found 227.3(M+1)⁺; Retention time: 0.86 minutes (3 min run).

Preparation of(4-isopropoxy-3-methyl-phenyl)-[10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone

To 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane(hydrochloride salt) (150 mg, 0.39 mmol) and4-isopropoxy-3-methyl-benzoic acid (75 mg, 0.39 mmol) in DMF (1 mL) wasadded at room temperatureO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (162 mg, 0.43 mmol) and diisopropylethylamine (337μL, 1.94 mmol) and reaction mixture was stirred at room temperature for30 minutes. The reaction was diluted with ethyl acetate and washed with1M NaOH and then brine solution. The organic layer was separated, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby silica gel column chromatography using 10-60% EtOAc/hexane to givethe desired compound as a white foam (147 mg, 73%) ESI-MS m/z calc.490.2. found 491.4 (M+1)⁺; Retention time: 2.42 minutes (3 min run).

The following compounds were made using Method A as described above:

Names Acid names Amine Names (3-chloro-4-isopropoxy-3-chloro-4-isopropoxy- 10-phenyl-8-(2,2,2- phenyl)-[10-phenyl-8- benzoicacid trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(4-isopropoxy-3-methyl- 4-isopropoxy-3-methyl- 10-phenyl-8-(2,2,2-phenyl)-[10-phenyl-8- benzoic acid trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (3-fluoro-4-isopropoxy-3-fluoro-4-isopropoxy- 10-phenyl-8-(2,2,2- phenyl)-[10-phenyl-8- benzoicacid trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone[4-(2-methoxy-2-methyl- 4-(2-methoxy-2-methyl- 10-phenyl-8-(2,2,2-propoxy)phenyl]-[10- propoxy)benzoic acid trifluoroethyl)-11-oxa-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone (4-isopropoxy-3-4-isopropoxy-3-methoxy- 10-phenyl-8-(2,2,2- methoxy-phenyl)-[10- benzoicacid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (5-isopropoxy-6-methyl-5-isopropoxy-6-methyl- 10-phenyl-8-(2,2,2- 2-pyridyl)-[10-phenyl-8-pyridine-2-carboxylic trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11-acid 3,8- oxa-3,8- diazaspiro[5.5]undecane diazaspiro[5.5]undecan-3-yl]methanone (4- 4-isobutylsulfonylbenzoic 10-phenyl-8-(2,2,2-isobutylsulfonylphenyl)- acid trifluoroethyl)-11-oxa-[10-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa-diazaspiro[5.5]undecane 3,8- diazaspiro[5.5]undecan- 3-yl]methanone[4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2-methyl- 10-phenyl-8-(2,2,2-propoxy)-3-methyl- propoxy)-3-methyl- trifluoroethyl)-11-oxa-phenyl]-[10-phenyl-8- benzoic acid 3,8- (2,2,2-trifluoroethyl)-11-diazaspiro[5.5]undecane oxa-3,8- diazaspiro[5.5]undecan- 3-yl]methanone(4-isopropylsulfonyl-3- 4-isopropylsulfonyl-3- 10-phenyl-8-(2,2,2-methyl-phenyl)-[10- methyl-benzoic acid trifluoroethyl)-11-oxa-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone (3-methyl-4-morpholino-3-methyl-4-morpholino- 10-phenyl-8-(2,2,2- phenyl)-[10-phenyl-8- benzoicacid trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(5-isopropoxy-2- 5-isopropoxypyridine-2- 10-phenyl-8-(2,2,2-pyridyl)-[10-phenyl-8- carboxylic acid trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (2-fluoro-4-isopropoxy-2-fluoro-4-isopropoxy- 10-phenyl-8-(2,2,2- phenyl)-[10-phenyl-8- benzoicacid trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone[3-methyl-4-(oxetan-3- 3-methyl-4-(oxetan-3- 10-phenyl-8-(2,2,2-yloxy)phenyl]-[10- yloxy)benzoic acid trifluoroethyl)-11-oxa-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone [3-methoxy-4-(2-3-methoxy-4-(2- 10-phenyl-8-(2,2,2- methoxyethoxy)phenyl]-methoxyethoxy)benzoic trifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- acid3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [3-(hydroxymethyl)-4-3-(hydroxymethyl)-4- 10-phenyl-8-(2,2,2- isopropoxy-phenyl]-[10-isopropoxy-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (4-isopropoxyphenyl)-4-isopropoxybenzoic acid 10-phenyl-8-(2,2,2- [10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(4-ethylsulfonyl-3- 4-ethylsulfonyl-3-methyl- 10-phenyl-8-(2,2,2-methyl-phenyl)-[10- benzoic acid trifluoroethyl)-11-oxa-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone (4-tert- 4-tert-10-phenyl-8-(2,2,2- butylsulfonylphenyl)- butylsulfonylbenzoic acidtrifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1-hydroxy-1-methyl-4-(1-hydroxy-1-methyl- 10-phenyl-8-(2,2,2- ethyl)-3-methyl-phenyl]-ethyl)-3-methyl-benzoic trifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2-acid 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (4-tert-butoxy-3-4-tert-butoxy-3-methoxy- 10-phenyl-8-(2,2,2- methoxy-phenyl)-[10-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (3-fluoro-4-isopropoxy-3-fluoro-4-isopropoxy-5- 10-phenyl-8-(2,2,2- 5-methoxy-phenyl)-[10-methoxy-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone N-cyclopropyl-4-[10- 4-10-phenyl-8-(2,2,2- phenyl-8-(2,2,2- (cyclopropylsulfamoyl)benzoictrifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa- acid 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecane- 3-carbonyl]benzenesulfonamide [4-(2-hydroxy-2-methyl-4-(2-hydroxy-2-methyl- 10-phenyl-8-(2,2,2- propyl)phenyl]-[10-propyl)benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (3-methyl-4- 3-methyl-4-10-phenyl-8-(2,2,2- methylsulfonyl-phenyl)- methylsulfonyl-benzoictrifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- acid 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [3-methyl-4-(oxetan-3-3-methyl-4-(oxetan-3- 10-phenyl-8-(2,2,2- yl)phenyl]-[10-phenyl-8-yl)benzoic acid trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8-oxa-3,8- diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(2-methyl-1,3- 2-methyl-1,3- 10-phenyl-8-(2,2,2- benzoxazol-7-yl)-[10-benzoxazole-7-carboxylic trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- acid3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1-hydroxy-1-methyl-4-(1-hydroxy-1-methyl- 10-phenyl-8-(2,2,2- ethyl)phenyl]-[10-ethyl)benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [3-fluoro-4-(1-hydroxy-3-fluoro-4-(1-hydroxy-1- 10-phenyl-8-(2,2,2- 1-methyl-ethyl)phenyl]-methyl-ethyl)benzoic acid trifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2-3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone N,N-diethyl-2-fluoro-4-4-(diethylcarbamoyl)-3- 10-phenyl-8-(2,2,2- [10-phenyl-8-(2,2,2-fluoro-benzoic acid trifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa- 3,8-3,8- diazaspiro[5.5]undecane diazaspiro[5.5]undecane-3-carbonyl]benzamide (5-tert-butoxy-2- 5-tert-butoxypyridine-2-10-phenyl-8-(2,2,2- pyridyl)-[10-phenyl-8- carboxylic acidtrifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone[4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2-methyl- 10-phenyl-8-(2,2,2-propoxy)phenyl]-[10- propoxy)benzoic acid trifluoroethyl)-11-oxa-phenyl-8-(2,2,2- 3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone [3-fluoro-4-(2-hydroxy-3-fluoro-4-(2-hydroxy-2- 10-phenyl-8-(2,2,2- 2-methyl-propyl)phenyl]-methyl-propyl)benzoic trifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- acid3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone methyl 2-[2-methoxy-4-3-methoxy-4-(2-methoxy- 10-phenyl-8-(2,2,2- [10-phenyl-8-(2,2,2-1,1-dimethyl-2-oxo- trifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa-ethyl)benzoic acid 3,8- 3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecane- 3-carbonyl]phenyl]-2- methyl-propanoate[3-fluoro-4-(3- 3-fluoro-4-(3- 10-phenyl-8-(2,2,2- methoxyprop-1-methoxyprop-1- trifluoroethyl)-11-oxa- ynyl)phenyl]-[10-phenyl-ynyl)benzoic acid 3,8- 8-(2,2,2-trifluoroethyl)- diazaspiro[5.5]undecane11-oxa-3,8- diazaspiro[5.5]undecan- 3-yl]methanone (3-chlorophenyl)-[10-3-chlorobenzoic acid 10-phenyl-8-(2,2,2- phenyl-8-(2,2,2-trifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone[4-(3-hydroxyoxetan-3- 4-(3-hydroxyoxetan-3- 10-phenyl-8-(2,2,2-yl)phenyl]-[10-phenyl-8- yl)benzoic acid trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (2-methyl-4- 2-methyl-4-10-phenyl-8-(2,2,2- methylsulfonyl-phenyl)- methylsulfonyl-benzoictrifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- acid 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone 2-methyl-6-[10-phenyl-8-5-cyano-6-methyl- 10-phenyl-8-(2,2,2- (2,2,2-trifluoroethyl)-11-pyridine-2-carboxylic trifluoroethyl)-11-oxa- oxa-3,8- acid 3,8-diazaspiro[5.5]undecane- diazaspiro[5.5]undecane 3-carbonyl]pyridine-3-carbonitrile (3-methoxy-4- 3-methoxy-4- 10-phenyl-8-(2,2,2-methylsulfonyl-phenyl)- methylsulfonyl-benzoic trifluoroethyl)-11-oxa-[10-phenyl-8-(2,2,2- acid 3,8- trifluoroethyl)-11-oxa-diazaspiro[5.5]undecane 3,8- diazaspiro[5.5]undecan- 3-yl]methanone(3-fluoro-5-methoxy- 3-fluoro-5-methoxy- 10-phenyl-8-(2,2,2-phenyl)-[10-phenyl-8- benzoic acid trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone [2- 2- 10-phenyl-8-(2,2,2-(difluoromethoxy)phenyl]- (difluoromethoxy)benzoictrifluoroethyl)-11-oxa- [10-phenyl-8-(2,2,2- acid 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [2-(difluoromethoxy)-3-2-(difluoromethoxy)-3- 10-phenyl-8-(2,2,2- fluoro-phenyl]-[10-fluoro-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (3,5-dichlorophenyl)-[10-3,5-dichlorobenzoic acid 10-phenyl-8-(2,2,2- phenyl-8-(2,2,2-trifluoroethyl)-11-oxa- trifluoroethyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(3-chloro-4-isopropoxy- 3-chloro-4-isopropoxy- 8-(2,2-difluoroethyl)-10-phenyl)-[8-(2,2- benzoic acid phenyl-11-oxa-3,8-difluoroethyl)-10-phenyl- diazaspiro[5.5]undecane 11-oxa-3,8-diazaspiro[5.5]undecan- 3-yl]methanone [8-(2,2-difluoroethyl)-10-3-fluoro-4-isopropoxy- 8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8-benzoic acid phenyl-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8- benzoic acidphenyl-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 5-isopropoxy-6-methyl-8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8- pyridine-2-carboxylicphenyl-11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-(5-isopropoxy-6- methyl-2- pyridyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methoxy-8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8- benzoic acidphenyl-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-(1-hydroxy-1-methyl-8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8- ethyl)-3-methoxy-benzoicphenyl-11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[4-(1-hydroxy-1- methyl-ethyl)-3- methoxy- phenyl]methanone[8-(2,2-difluoroethyl)-10- 4-(1-hydroxy-1-methyl-8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8- ethyl)-3-methyl-benzoicphenyl-11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[4-(1-hydroxy-1- methyl-ethyl)-3-methyl- phenyl]methanone[8-(2,2-difluoroethyl)-10- 4-pyrrolidin-1- 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8- ylsulfonylbenzoic acid (2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-pyrrolidin-1-ylsulfonylphenyl)- methanone [8-(2,2-difluoroethyl)-10-4-(1-hydroxy-1-methyl- 8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8-ethyl)benzoic acid phenyl-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[4-(1-hydroxy-1- methyl-ethyl)phenyl]methanone [3-ethoxy-4- 3-ethoxy-4- 8-ethyl-10-phenyl-11-(hydroxymethyl)phenyl]- (hydroxymethyl)benzoic oxa-3,8-(8-ethyl-10-phenyl-11- acid diazaspiro[5.5]undecane oxa-3,8-diazaspiro[5.5]undecan- 3-yl)methanone [8-(2,2-difluoroethyl)-10-6-methoxypyridine-2- 8-(2,2-difluoroethyl)-10- phenyl-11-oxa-3,8-carboxylic acid phenyl-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(6-methoxy-2- pyridyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropylsulfonyl-3-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- methyl-benzoic acid(2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4- isopropylsulfonyl-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 5- 8-(2,2-difluoroethyl)-10-phenyl-11-oxa-3,8- (trifluoromethyl)pyridine- phenyl-11-oxa-3,8-diazaspiro[5.5]undecan- 2-carboxylic acid diazaspiro[5.5]undecane3-yl]-[5- (trifluoromethyl)-2- pyridyl]methanone6-[8-(2,2-difluoroethyl)- 5-cyano-6-methyl- 8-(2,2-difluoroethyl)-10-10-phenyl-11-oxa-3,8- pyridine-2-carboxylic phenyl-11-oxa-3,8-diazaspiro[5.5]undecane- acid diazaspiro[5.5]undecane3-carbonyl]-2-methyl- pyridine-3-carbonitrile [8-(2,2-difluoroethyl)-10-4-isopropoxy-3-methyl- 8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8-benzoic acid (2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- benzoic acid(2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone (3-chloro-4-isopropoxy-3-chloro-4-isopropoxy- 8-(2,2-difluoroethyl)-10- phenyl)-[8-(2,2-benzoic acid (2-pyridyl)-11-oxa-3,8- difluoroethyl)-10-(2-diazaspiro[5.5]undecane pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan-3-yl]methanone [8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methoxy-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- benzoic acid(2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-5-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- methoxy-benzoic acid(2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(3-fluoro-4- isopropoxy-5-methoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-(1-hydroxy-1-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- methyl-ethyl)benzoicacid (2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[3-fluoro-4-(1- hydroxy-1-methyl-ethyl)phenyl]methanone [8-(2,2-difluoroethyl)-10- 4-(2-hydroxyethoxy)-3-8-(2,2-difluoroethyl)-10- (2-pyridyl)-11-oxa-3,8- methyl-benzoic acid(2-pyridyl)-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-[4-(2- hydroxyethoxy)-3- methyl- phenyl]methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-8-(2,2-difluoroethyl)-10- (1H-pyrazol-3-yl)-11- benzoic acid(1H-pyrazol-3-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (1-methylpyrazol-3-yl)- benzoic acid(1-methylpyrazol-3-yl)- 11-oxa-3,8- 11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (2-methylpyrazol-3-yl)- benzoic acid(2-methylpyrazol-3-yl)- 11-oxa-3,8- 11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (1H-pyrazol-3-yl)-11- benzoic acid(1H-pyrazol-3-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone(4-isopropoxy-3-methyl- 4-isopropoxy-3-methyl- 10-(1H-pyrazol-3-yl)-8-phenyl)-[10-(1H-pyrazol- benzoic acid (2,2,2-trifluoroethyl)-11-3-yl)-8-(2,2,2- oxa-3,8- trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone (3-chloro-4-isopropoxy-3-chloro-4-isopropoxy- 10-(1H-pyrazol-3-yl)-8- phenyl)-[10-(1H-pyrazol-benzoic acid (2,2,2-trifluoroethyl)-11- 3-yl)-8-(2,2,2- oxa-3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [8-(2,2-difluoroethyl)-10-4-isopropoxy-3-methyl- 8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11- benzoic acid (1-ethylpyrazol-3-yl)-11-oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methoxy-8-(2,2-difluoroethyl)-10- (1H-pyrazol-3-yl)-11- benzoic acid(1H-pyrazol-3-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methoxy- phenyl)methanone[10-(5-tert-butyloxazol- 4-isopropoxy-3-methyl-10-(5-tert-butyloxazol-2- 2-yl)-8-(2,2- benzoic acidyl)-8-(2,2-difluoroethyl)- difluoroethyl)-11-oxa- 11-oxa-3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]-(4-isopropoxy-3-methyl- phenyl)methanone [10-(5-tert-butyloxazol- 3-fluoro-4-isopropoxy-10-(5-tert-butyloxazol-2- 2-yl)-8-(2,2- benzoic acidyl)-8-(2,2-difluoroethyl)- difluoroethyl)-11-oxa- 11-oxa-3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone [8-(2,2-difluoroethyl)-10-4-isopropoxy-3-methoxy- 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- benzoic acid (4-fluorophenyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3-methoxy- phenyl)methanone [8-(2,2-difluoroethyl)-10-4-isopropoxy-3-methyl- 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- benzoic acid (4-fluorophenyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3-methyl- phenyl)methanone (3-chloro-4-isopropoxy- 3-chloro-4-isopropoxy-8-(2,2-difluoroethyl)-10- phenyl)-[8-(2,2- benzoic acid(4-fluorophenyl)-11-oxa- difluoroethyl)-10-(4- 3,8-fluorophenyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [8-(2,2-difluoroethyl)-10-3-fluoro-4-isopropoxy- 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- benzoic acid (4-fluorophenyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone [8-(2,2-difluoroethyl)-10-3-fluoro-4-(1-hydroxy-1- 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- methyl-ethyl)benzoic acid(4-fluorophenyl)-11-oxa- 3,8- 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[3-fluoro-4-(1- hydroxy-1-methyl-ethyl)phenyl]methanone [8-(2,2-difluoroethyl)-10- 4-(2-hydroxy-2-methyl-8-(2,2-difluoroethyl)-10- (4-fluorophenyl)-11-oxa- propoxy)-3-methyl-(4-fluorophenyl)-11-oxa- 3,8- benzoic acid 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[4-(2-hydroxy-2- methyl-propoxy)-3-methyl- phenyl]methanone [8-(2,2-difluoroethyl)-10-4-isobutylsulfonylbenzoic 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- acid (4-fluorophenyl)-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isobutylsulfonylphenyl)- methanone (4-tert- 4-tert-8-(2,2-difluoroethyl)-10- butylsulfonylphenyl)-[8- butylsulfonylbenzoicacid (4-fluorophenyl)-11-oxa- (2,2-difluoroethyl)-10-(4- 3,8-fluorophenyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (4-tert-butoxy-3-4-tert-butoxy-3-methoxy- 8-(2,2-difluoroethyl)-10-methoxy-phenyl)-[8-(2,2- benzoic acid (4-fluorophenyl)-11-oxa-difluoroethyl)-10-(4- 3,8- fluorophenyl)-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone N-cyclopropyl-4-[8-(2,2- 4-8-(2,2-difluoroethyl)-10- difluoroethyl)-10-(4-(cyclopropylsulfamoyl)benzoic (4-fluorophenyl)-11-oxa-fluorophenyl)-11-oxa- acid 3,8- 3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecane- 3-carbonyl]benzene- sulfonamide[8-(2,2-difluoroethyl)-10- 4-tetrahydrofuran-3-8-(2,2-difluoroethyl)-10- (4-fluorophenyl)-11-oxa- ylsulfonylbenzoicacid (4-fluorophenyl)-11-oxa- 3,8- 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-tetrahydrofuran- 3-ylsulfonylphenyl)-methanone [8-(2,2-difluoroethyl)-10- 3-(hydroxymethyl)-4-8-(2,2-difluoroethyl)-10- (4-fluorophenyl)-11-oxa- isopropoxy-benzoicacid (4-fluorophenyl)-11-oxa- 3,8- 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[3- (hydroxymethyl)-4- isopropoxy-phenyl]methanone [8-(2,2-difluoroethyl)-10- 3-methyl-4-8-(2,2-difluoroethyl)-10- (4-fluorophenyl)-11-oxa-methylsulfonyl-benzoic (4-fluorophenyl)-11-oxa- 3,8- acid 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-methyl-4-methylsulfonyl- phenyl)methanone [8-(2,2-difluoroethyl)-10-4-(3-hydroxypropoxy)-3- 8-(2,2-difluoroethyl)-10-(4-fluorophenyl)-11-oxa- methyl-benzoic acid (4-fluorophenyl)-11-oxa-3,8- 3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-[4-(3-hydroxypropoxy)-3- methyl- phenyl]methanone [8-(2,2-difluoroethyl)-10-3-fluoro-4-isopropoxy- 8-(2,2-difluoroethyl)-10- (1-methylpyrazol-3-yl)-benzoic acid (1-methylpyrazol-3-yl)- 11-oxa-3,8- 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone (3-fluoro-4-isopropoxy-3-fluoro-4-isopropoxy- 10-(5-methyl-1H- phenyl)-[10-(5-methyl- benzoicacid pyrazol-3-yl)-8-(2,2,2- 1H-pyrazol-3-yl)-8- trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (4-isopropoxy-3-methyl-4-isopropoxy-3-methyl- 10-(5-methyl-1H- phenyl)-[10-(5-methyl- benzoicacid pyrazol-3-yl)-8-(2,2,2- 1H-pyrazol-3-yl)-8- trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (3-fluoro-4-isopropoxy-3-fluoro-4-isopropoxy- 10-(1H-pyrazol-3-yl)-8- phenyl)-[10-(1H-pyrazol-benzoic acid (2,2,2-trifluoroethyl)-11- 3-yl)-8-(2,2,2- oxa-3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (8-isobutyl-10-phenyl-4-isopropoxy-3-methyl- 8-isobutyl-10-phenyl-11- 11-oxa-3,8- benzoic acidoxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone (8-ethyl-10-phenyl-11-6-isopropoxypyridine-3- 8-ethyl-10-phenyl-11- oxa-3,8- carboxylic acidoxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(6-isopropoxy-3- pyridyl)methanone (8-ethyl-10-phenyl-11-4-(1-hydroxy-1-methyl- 8-ethyl-10-phenyl-11- oxa-3,8- ethyl)benzoic acidoxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-[4-(1-hydroxy-1- methyl- ethyl)phenyl]methanone [4-ethoxy-3-4-ethoxy-3- 8-ethyl-10-phenyl-11- (hydroxymethyl)phenyl]-(hydroxymethyl)benzoic oxa-3,8- (8-ethyl-10-phenyl-11- aciddiazaspiro[5.5]undecane oxa-3,8- diazaspiro[5.5]undecan- 3-yl)methanone(8-ethyl-10-phenyl-11- 4-isopropoxy-3-methyl- 8-ethyl-10-phenyl-11-oxa-3,8- benzoic acid oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone(8-ethyl-10-phenyl-11- 4-isopropoxy-3-methoxy- 8-ethyl-10-phenyl-11-oxa-3,8- benzoic acid oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-(4-isopropoxy-3- methoxy- phenyl)methanone(8-ethyl-10-phenyl-11- 3-fluoro-4-isopropoxy- 8-ethyl-10-phenyl-11-oxa-3,8- benzoic acid oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-(3-fluoro-4- isopropoxy- phenyl)methanone(8-ethyl-10-phenyl-11- 3-(hydroxymethyl)-4- 8-ethyl-10-phenyl-11-oxa-3,8- isopropoxy-benzoic acid oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-[3- (hydroxymethyl)-4- isopropoxy-phenyl]methanone N-cyclopropyl-4-(8- 4- 8-ethyl-10-phenyl-11-ethyl-10-phenyl-11-oxa- (cyclopropylsulfamoyl)benzoic oxa-3,8- 3,8- aciddiazaspiro[5.5]undecane diazaspiro[5.5]undecane- 3-carbonyl)benzene-sulfonamide [8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- oxazol-2-yl-11-oxa-3,8- benzoic acidoxazol-2-yl-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-(1-hydroxy-1-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- methyl-ethyl)benzoicacid (6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[3-fluoro-4-(1- hydroxy-1-methyl-ethyl)phenyl]methanone [8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- benzoic acid(6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone(3-chloro-4-isopropoxy- 3-chloro-4-isopropoxy- 8-(2,2-difluoroethyl)-10-phenyl)-[8-(2,2- benzoic acid (6-methyl-2-pyridyl)-11-difluoroethyl)-10-(6- oxa-3,8- methyl-2-pyridyl)-11-diazaspiro[5.5]undecane oxa-3,8- diazaspiro[5.5]undecan- 3-yl]methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- benzoic acid(6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methoxy-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- benzoic acid(6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropylsulfonyl-3-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- methyl-benzoic acid(6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4- isopropylsulfonyl-3- methyl-phenyl)methanone [8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-5-8-(2,2-difluoroethyl)-10- (6-methyl-2-pyridyl)-11- methoxy-benzoic acid(6-methyl-2-pyridyl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy-5-methoxy-phenyl)methanone 2-[3-[4-(1-hydroxy-1- 4-(1-hydroxy-1-methyl-2-(10-phenyl-11-oxa- methyl-ethyl)benzoyl]- ethyl)benzoic acid 3,8-10-phenyl-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecan-8-yl)acetonitrile 8-yl]acetonitrile [4-(3-hydroxypropoxy)-4-(3-hydroxypropoxy)-3- 10-phenyl-8-(2,2,2- 3-methyl-phenyl]-[10-methyl-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone 2-[3-(5-isopropoxy-6-5-isopropoxy-6-methyl- 2-(10-phenyl-11-oxa- methyl-pyridine-2-pyridine-2-carboxylic 3,8- carbonyl)-10-phenyl-11- aciddiazaspiro[5.5]undecan- oxa-3,8- 8-yl)acetonitrilediazaspiro[5.5]undecan- 8-yl]acetonitrile [4-(2-hydroxyethoxy)-3-4-(2-hydroxyethoxy)-3- 10-phenyl-8-(2,2,2- methyl-phenyl]-[10-methyl-benzoic acid trifluoroethyl)-11-oxa- phenyl-8-(2,2,2- 3,8-trifluoroethyl)-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone 2-[3-[4-(1-hydroxy-1-4-(1-hydroxy-1-methyl- 2-(10-phenyl-11-oxa- methyl-ethyl)-3-ethyl)-3-methoxy-benzoic 3,8- methoxy-benzoyl]-10- aciddiazaspiro[5.5]undecan- phenyl-11-oxa-3,8- 8-yl)acetonitrilediazaspiro[5.5]undecan- 8-yl]acetonitrile 2-[3-[4-(1-hydroxy-1-4-(1-hydroxy-1-methyl- 2-(10-phenyl-11-oxa- methyl-ethyl)-3-methyl-ethyl)-3-methyl-benzoic 3,8- benzoyl]-10-phenyl-11- aciddiazaspiro[5.5]undecan- oxa-3,8- 8-yl)acetonitrilediazaspiro[5.5]undecan- 8-yl]acetonitrile 2-[3-(4-isopropoxy-3-4-isopropoxy-3-methyl- 2-(10-phenyl-11-oxa- methyl-benzoyl)-10- benzoicacid 3,8- phenyl-11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecan- 8-yl)acetonitrile 8-yl]acetonitrile2-[3-(4-isopropoxy-3- 4-isopropoxy-3-methoxy- 2-(10-phenyl-11-oxa-methoxy-benzoyl)-10- benzoic acid 3,8- phenyl-11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecan- 8-yl)acetonitrile8-yl]acetonitrile [8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (5-isopropyloxazol-2-yl)- benzoic acid(5-isopropyloxazol-2- 11-oxa-3,8- yl)-11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3-methyl- phenyl)methanone [8-ethyl-10-(4- 3-fluoro-4-isopropoxy-8-ethyl-10-(4- fluorophenyl)-11-oxa- benzoic acid fluorophenyl)-11-oxa-3,8- 3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone [8-tert-butyl-10-(5-4-isopropoxy-3-methyl- 8-tert-butyl-10-(5- methyloxazol-2-yl)-11-benzoic acid methyloxazol-2-yl)-11- oxa-3,8- oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3-methyl- phenyl)methanone [8-tert-butyl-10-(5- 3-fluoro-4-isopropoxy-8-tert-butyl-10-(5- methyloxazol-2-yl)-11- benzoic acidmethyloxazol-2-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone(8-ethyl-9-phenyl-11- 4-isopropoxy-3-methyl- 8-ethyl-9-phenyl-11-oxa-oxa-3,8- benzoic acid 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone(8-ethyl-9-phenyl-11- 4-isopropoxy-3-methoxy- 8-ethyl-9-phenyl-11-oxa-oxa-3,8- benzoic acid 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl)-(4-isopropoxy-3- methoxy- phenyl)methanone[8-ethyl-10-(5- 4-isopropoxy-3-methyl- 8-ethyl-10-(5-methylthiazol-2-yl)-11- benzoic acid methylthiazol-2-yl)-11- oxa-3,8-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone [8-ethyl-10-(5-4-isopropoxy-3-methoxy- 8-ethyl-10-(5- methylthiazol-2-yl)-11- benzoicacid methylthiazol-2-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3-methyl-8-(2,2-difluoroethyl)-10- (5-ethyloxazol-2-yl)-11- benzoic acid(5-ethyloxazol-2-yl)-11- oxa-3,8- oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone1-[3-(4-isopropoxy-3- 4-isopropoxy-3- 1-(2-phenyl-1-oxa-4,9-methyl-benzoyl)-10- methylbenzoic acid diazaspiro[5.5]undecan-phenyl-11-oxa-3,8- 4-yl)propan-1-one diazaspiro[5.5]undecan-8-yl]propan-1-one [8-(2,2-difluoroethyl)-10- 3-fluoro-4-isopropoxy-8-(2,2-difluoroethyl)-10- (5-isopropyloxazol-2-yl)- benzoic acid(5-isopropyloxazol-2- 11-oxa-3,8- yl)-11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone (8-ethyl-10,10-dimethyl-4-isopropoxy-3-methyl- 8-ethyl-10,10-dimethyl- 11-oxa-3,8- benzoic acid11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone (8,9-diethyl-11-oxa-3,8-4-isopropoxy-3-methyl- 8,9-diethyl-11-oxa-3,8- diazaspiro[5.5]undecan-benzoic acid diazaspiro[5.5]undecane 3-yl)-(4-isopropoxy-3- methyl-phenyl)methanone (4-isopropoxy-3-methyl- 4-isopropoxy-3-methyl-10-(5-methylthiazol-2- phenyl)-[10-(5- benzoic acid yl)-8-(2,2,2-methylthiazol-2-yl)-8- trifluoroethyl)-11-oxa-(2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl]methanone (4-isopropoxy-3-4-isopropoxy-3-methoxy- 10-(5-methylthiazol-2- methoxy-phenyl)-[10-(5-benzoic acid yl)-8-(2,2,2- methylthiazol-2-yl)-8-trifluoroethyl)-11-oxa- (2,2,2-trifluoroethyl)-11- 3,8- oxa-3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3- 4-(2,2-difluoroethyl)-2-(2-fluorophenyl)-11-oxa- methylbenzoic acid (2-fluorophenyl)-1-oxa- 3,8-4,9- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone [8-(2,2-difluoroethyl)-10- 3-fluoro-4-4-(2,2-difluoroethyl)-2- (2-fluorophenyl)-11-oxa- isopropoxybenzoic acid(2-fluorophenyl)-1-oxa- 3,8- 4,9- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4- 4-(2,2-difluoroethyl)-2-oxazol-2-yl-11-oxa-3,8- isopropoxybenzoic acid (oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4-isopropoxy- phenyl)methanone [8-(2,2-difluoroethyl)-10- 3-fluoro-4-4-(2,2-difluoroethyl)-2- (3-methyl-2-pyridyl)-11- isopropoxybenzoic acid(3-methylpyridin-2-yl)- oxa-3,8- 1-oxa-4,9- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone[8-(2,2-difluoroethyl)-10- 4-isopropoxy-3- 4-(2,2-difluoroethyl)-2-(4-methyl-1H-pyrazol-5- methylbenzoic acid (4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8- yl)-1-oxa-4,9- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoroethyl)-10- 3-fluoro-4- 4-(2,2-difluoroethyl)-2-(4-methyl-1H-pyrazol-5- isopropoxybenzoic acid (4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8- yl)-1-oxa-4,9- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(3-fluoro-4- isopropoxy- phenyl)methanone[8-tert-butyl-10- 4-isopropoxy-3-methyl- 8-tert-butyl-10-(methoxymethyl)-11- benzoic acid (methoxymethyl)-11- oxa-3,8- oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3-methyl- phenyl)methanone (8-tert-butyl-10-ethyl-11-4-isopropoxy-3-methyl- 8-tert-butyl-10-ethyl-11- oxa-3,8- benzoic acidoxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone (8-but-2-ynyl-10-ethyl-4-methoxy-3- 8-but-2-ynyl-10-ethyl- 11-oxa-3,8- (trifluoromethyl)benzoic11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl)-[4-methoxy-3- (trifluoromethyl)phenyl]methanone(8-but-2-ynyl-10-ethyl- 5-isopropoxy-6-methyl- 8-but-2-ynyl-10-ethyl-11-oxa-3,8- pyridine-2-carboxylic 11-oxa-3,8- diazaspiro[5.5]undecan-acid diazaspiro[5.5]undecane 3-yl)-(5-isopropoxy-6- methyl-2-pyridyl)methanone 5-(8-but-2-ynyl-10-ethyl- 3-cyano-4-isopropoxy-8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecane- diazaspiro[5.5]undecane 3-carbonyl)-2-isopropoxy-benzonitrile (8-but-2-ynyl-10-ethyl- 3-chloro-4-isopropoxy-8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl)-(3-chloro-4-isopropoxy- phenyl)methanone (8-but-2-ynyl-10-ethyl-3-fluoro-4-isopropoxy- 8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(3-fluoro-4- isopropoxy- phenyl)methanone (4-tert-butyl-3-methoxy-4-tert-butyl-3-methoxy- 8-but-2-ynyl-10-ethyl- phenyl)-(8-but-2-ynyl-benzoic acid 11-oxa-3,8- 10-ethyl-11-oxa-3,8- diazaspiro[5.5]undecanediazaspiro[5.5]undecan- 3-yl)methanone [4-(1- 4-(1-10-(methoxymethyl)-8- hydroxycyclobutyl)phenyl]-hydroxycyclobutyl)benzoic [3- [10-(methoxymethyl)- acid(trifluoromethyl)phenyl]- 8-[3- 11-oxa-3,8- (trifluoromethyl)phenyl]-diazaspiro[5.5]undecane 11-oxa-3,8- diazaspiro[5.5]undecan-3-yl]methanone [4-(2-hydroxy-2-methyl- 4-(2-hydroxy-2-methyl-10-(methoxymethyl)-8- propoxy)-3-methyl- propoxy)-3-methyl- [3-phenyl]-[10- benzoic acid (trifluoromethyl)phenyl]-(methoxymethyl)-8-[3- 11-oxa-3,8- (trifluoromethyl)phenyl]-diazaspiro[5.5]undecane 11-oxa-3,8- diazaspiro[5.5]undecan-3-yl]methanone (10-ethyl-8-pyrimidin-2- 4-(1-hydroxycyclobutyl)-10-ethyl-8-pyrimidin-2- yl-11-oxa-3,8- 3-methyl-benzoic acidyl-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-[4-(1- hydroxycyclobutyl)-3- methyl- phenyl]methanone[10-ethyl-8-(2-pyridyl)- 4-(1-hydroxycyclobutyl)-10-ethyl-8-(2-pyridyl)- 11-oxa-3,8- 3-methyl-benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-[4-(1-hydroxycyclobutyl)-3- methyl- phenyl]methanone [4-(1-4-(1-hydroxycyclobutyl)- 10-(methoxymethyl)-8- hydroxycyclobutyl)-3-3-methyl-benzoic acid pyrimidin-2-yl-11-oxa- methyl-phenyl]-[10- 3,8-(methoxymethyl)-8- diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [10-ethyl-8-(2-pyridyl)- 4-(1-10-ethyl-8-(2-pyridyl)- 11-oxa-3,8- hydroxycyclohexyl)benzoic11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[4-(1- hydroxycyclohexyl)- phenyl]methanone(10-ethyl-8-pyrimidin-2- 4-(1- 10-ethyl-8-pyrimidin-2- yl-11-oxa-3,8-hydroxycyclohexyl)benzoic yl-11-oxa-3,8- diazaspiro[5.5]undecan- aciddiazaspiro[5.5]undecane 3-yl)-[4-(1- hydroxycyclohexyl)-phenyl]methanone [4-(1- 4-(1- 10-(methoxymethyl)-8- hydroxycyclohexyl)-hydroxycyclohexyl)benzoic pyrimidin-2-yl-11-oxa- phenyl]-[10- acid 3,8-(methoxymethyl)-8- diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [10-ethyl-8-(2-pyridyl)- 4-(1-10-ethyl-8-(2-pyridyl)- 11-oxa-3,8- hydroxycyclopentyl)benzoic11-oxa-3,8- diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[4-(1- hydroxycyclopentyl)phenyl]methanone[10-ethyl-8-(2-pyridyl)- 3-fluoro-4-(1- 10-ethyl-8-(2-pyridyl)-11-oxa-3,8- hydroxycyclopentyl)benzoic 11-oxa-3,8-diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[3-fluoro-4-(1- hydroxycyclopentyl)- phenyl]methanone[10-ethyl-8-(2-pyridyl)- 4-(1- 10-ethyl-8-(2-pyridyl)- 11-oxa-3,8-hydroxycyclopentyl)-3- 11-oxa-3,8- diazaspiro[5.5]undecan-methyl-benzoic acid diazaspiro[5.5]undecane 3-yl]-[4-(1-hydroxycyclopentyl)-3- methyl- phenyl]methanone [10-ethyl-8-(2-pyridyl)-3-fluoro-4-(1-hydroxy-1- 10-ethyl-8-(2-pyridyl)- 11-oxa-3,8-methyl-ethyl)benzoic acid 11-oxa-3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-[3-fluoro-4-(1- hydroxy-1-methyl-ethyl)phenyl]methanone [10-ethyl-8-(2-pyridyl)- 4-(1-hydroxy-1-methyl-10-ethyl-8-(2-pyridyl)- 11-oxa-3,8- ethyl)-3-methyl-benzoic 11-oxa-3,8-diazaspiro[5.5]undecan- acid diazaspiro[5.5]undecane3-yl]-[4-(1-hydroxy-1- methyl-ethyl)-3-methyl- phenyl]methanone(10-ethyl-8-pyrimidin-2- 4-isopropylsulfonyl-3- 10-ethyl-8-pyrimidin-2-yl-11-oxa-3,8- methyl-benzoic acid yl-11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl)-(4-isopropylsulfonyl-3- methyl- phenyl)methanone (10-ethyl-8-pyrimidin-2-3-fluoro-4-(1- 10-ethyl-8-pyrimidin-2- yl-11-oxa-3,8-hydroxycyclopentyl)benzoic yl-11-oxa-3,8- diazaspiro[5.5]undecan- aciddiazaspiro[5.5]undecane 3-yl)-[3-fluoro-4-(1- hydroxycyclopentyl)-phenyl]methanone [4-(1-ethyl-1-hydroxy- 4-(1-ethyl-1-hydroxy-10-ethyl-8-pyrimidin-2- propyl)-3-methyl- propyl)-3-methyl-benzoicyl-11-oxa-3,8- phenyl]-(10-ethyl-8- acid diazaspiro[5.5]undecanepyrimidin-2-yl-11-oxa- 3,8- diazaspiro[5.5]undecan- 3-yl)methanone(10-ethyl-8-pyrimidin-2- 4-(1- 10-ethyl-8-pyrimidin-2- yl-11-oxa-3,8-hydroxycyclopentyl)-3- yl-11-oxa-3,8- diazaspiro[5.5]undecan-methyl-benzoic acid diazaspiro[5.5]undecane 3-yl)-[4-(1-hydroxycyclopentyl)-3- methyl- phenyl]methanone [4-(1- 4-(1-10-(methoxymethyl)-8- hydroxycyclopentyl)-3- hydroxycyclopentyl)-3-pyrimidin-2-yl-11-oxa- methyl-phenyl]-[10- methyl-benzoic acid 3,8-(methoxymethyl)-8- diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1- 4-(1-10-(methoxymethyl)-8- hydroxycyclopentyl)- hydroxycyclopentyl)benzoicpyrimidin-2-yl-11-oxa- phenyl]-[10- acid 3,8- (methoxymethyl)-8-diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1- 4-(1-10-(methoxymethyl)-8- hydroxycyclobutyl)- hydroxycyclobutyl)benzoicpyrimidin-2-yl-11-oxa- phenyl]-[10- acid 3,8- (methoxymethyl)-8-diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(2-hydroxy-2-methyl-4-(2-hydroxy-2-methyl- 10-(methoxymethyl)-8- propoxy)-3-methyl-propoxy)-3-methyl- pyrimidin-2-yl-11-oxa- phenyl]-[10- benzoic acid 3,8-(methoxymethyl)-8- diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone 2-isopropoxy-5-[10-3-cyano-4-isopropoxy- 10-(methoxymethyl)-8- (methoxymethyl)-8- benzoicacid pyrimidin-2-yl-11-oxa- pyrimidin-2-yl-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecane- 3-carbonyl]benzonitrile(4-tert-butyl-3-methoxy- 4-tert-butyl-3-methoxy- 10-(methoxymethyl)-8-phenyl)-[10- benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [3-methoxy-4-(2- 3-methoxy-4-(2-10-(methoxymethyl)-8- methoxyethoxy)phenyl]- methoxyethoxy)benzoicpyrimidin-2-yl-11-oxa- [10-(methoxymethyl)-8- acid 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (5-isopropoxy-6-methyl-5-isopropoxy-6-methyl- 10-(methoxymethyl)-8- 2-pyridyl)-[10-pyridine-2-carboxylic pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- acid3,8- pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (3-ethoxyphenyl)-[10-3-ethoxybenzoic acid 10-(methoxymethyl)-8- (methoxymethyl)-8-pyrimidin-2-yl-11-oxa- pyrimidin-2-yl-11-oxa- 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(4-isopropoxyphenyl)- 4-isopropoxybenzoic acid 10-(methoxymethyl)-8-[10-(methoxymethyl)-8- pyrimidin-2-yl-11-oxa- pyrimidin-2-yl-11-oxa-3,8- 3,8- diazaspiro[5.5]undecane diazaspiro[5.5]undecan- 3-yl]methanone(4- 4- 10-(methoxymethyl)-8- cyclopropylsulfonylphenyl)-cyclopropylsulfonylbenzoic pyrimidin-2-yl-11-oxa- [10- acid 3,8-(methoxymethyl)-8- diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1-hydroxy-1-methyl-4-(1-hydroxy-1-methyl- 10-(methoxymethyl)-8- ethyl)-3-methyl-phenyl]-ethyl)-3-methyl-benzoic pyrimidin-2-yl-11-oxa- [10-(methoxymethyl)-8-acid 3,8- pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(1-hydroxy-1-methyl-4-(1-hydroxy-1-methyl- 10-(methoxymethyl)-8- ethyl)phenyl]-[10-ethyl)benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [3-fluoro-4-(1-hydroxy-3-fluoro-4-(1-hydroxy-1- 10-(methoxymethyl)-8- 1-methyl-ethyl)phenyl]-methyl-ethyl)benzoic acid pyrimidin-2-yl-11-oxa- [10-(methoxymethyl)-8-3,8- pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (3-fluoro-4-isopropoxy-3-fluoro-4-isopropoxy- 10-(methoxymethyl)-8- phenyl)-[10- benzoic acidpyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8- pyrimidin-2-yl-11-oxa-diazaspiro[5.5]undecane 3,8- diazaspiro[5.5]undecan- 3-yl]methanone(4-isopentyloxy-3- 4-isopentyloxy-3- 10-(methoxymethyl)-8-methoxy-phenyl)-[10- methoxy-benzoic acid pyrimidin-2-yl-11-oxa-(methoxymethyl)-8- 3,8- pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane3,8- diazaspiro[5.5]undecan- 3-yl]methanone [4-(1-hydroxy-2-methyl-4-(1-hydroxy-2-methyl- 10-(methoxymethyl)-8- propyl)phenyl]-[10-propyl)benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [2-(difluoromethoxy)- 2-10-(methoxymethyl)-8- phenyl]-[10- (difluoromethoxy)benzoicpyrimidin-2-yl-11-oxa- (methoxymethyl)-8- acid 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4-(2-hydroxy-2-methyl-4-(2-hydroxy-2-methyl- 10-(methoxymethyl)-8- propyl)phenyl]-[10-propyl)benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [4- 4- 10-(methoxymethyl)-8-(difluoromethylsulfonyl)phenyl]- (difluoromethylsulfonyl)benzoicpyrimidin-2-yl-11-oxa- [10- acid 3,8- (methoxymethyl)-8-diazaspiro[5.5]undecane pyrimidin-2-yl-11-oxa- 3,8-diazaspiro[5.5]undecan- 3-yl]methanone [10-(methoxymethyl)-8-4-methoxy-3- 10-(methoxymethyl)-8- pyrimidin-2-yl-11-oxa-(trifluoromethyl)benzoic pyrimidin-2-yl-11-oxa- 3,8- acid 3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl]-[4-methoxy-3-(trifluoromethyl)phenyl]methanone [3-(hydroxymethyl)-4-3-(hydroxymethyl)-4- 10-(methoxymethyl)-8- isopropoxy-phenyl]-[10-isopropoxy-benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone (4-isopropoxy-3-4-isopropoxy-3-methoxy- 10-(methoxymethyl)-8- methoxy-phenyl)-[10-benzoic acid pyrimidin-2-yl-11-oxa- (methoxymethyl)-8- 3,8-pyrimidin-2-yl-11-oxa- diazaspiro[5.5]undecane 3,8-diazaspiro[5.5]undecan- 3-yl]methanone N-cyclopropyl-4-[10- 4-10-(methoxymethyl)-8- (methoxymethyl)-8- (cyclopropylsulfamoyl)benzoicpyrimidin-2-yl-11-oxa- pyrimidin-2-yl-11-oxa- acid 3,8- 3,8-diazaspiro[5.5]undecane diazaspiro[5.5]undecane- 3-carbonyl]benzene-sulfonamide (8-but-2-ynyl-10-ethyl- 3-methyl-4-propoxy-8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl)-(3-methyl-4-propoxy- phenyl)methanone (8-but-2-ynyl-10-ethyl- 4-ethoxy-3-methyl-8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl)-(4-ethoxy-3-methyl- phenyl)methanone (8-but-2-ynyl-10-ethyl- 4-methoxy-3-methyl-8-but-2-ynyl-10-ethyl- 11-oxa-3,8- benzoic acid 11-oxa-3,8-diazaspiro[5.5]undecan- diazaspiro[5.5]undecane 3-yl)-(4-methoxy-3-methyl- phenyl)methanone [3-fluoro-4-(1-hydroxy-3-fluoro-4-(1-hydroxy-1- [10-(methoxymethyl)-8- 1-methyl-ethyl)phenyl]-methyl-ethyl)benzoic acid [3- 10-(methoxymethyl)-8-(trifluoromethyl)phenyl]- [3- 11-oxa-3,8- (trifluoromethyl)phenyl]-diazaspiro[5.5]undecane 11-oxa-3,8- diazaspiro[5.5]undecan-3-yl]methanone (8-but-2-ynyl-10,10- 4-isopropoxy-3-methyl-8-but-2-ynyl-10,10- difluoro-11-oxa-3,8- benzoic aciddifluoro-11-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl)-(4-isopropoxy-3- methyl- phenyl)methanone [8-but-2-ynyl-10-4-isopropoxy-3-methyl- 8-but-2-ynyl-10- (fluoromethyl)-11-oxa- benzoicacid (fluoromethyl)-11-oxa- 3,8- 3,8- diazaspiro[5.5]undecan-diazaspiro[5.5]undecane 3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone[8-(2,2-difluoropropyl)- 4-isopropoxy-3-methyl- 8-(2,2-difluoropropyl)-10-(methoxymethyl)-11- benzoic acid 10-(methoxymethyl)-11- oxa-3,8-oxa-3,8- diazaspiro[5.5]undecan- diazaspiro[5.5]undecane3-yl]-(4-isopropoxy-3- methyl- phenyl)methanone

Preparation of(4-isopropoxy-3-methyl-phenyl)-(10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone

Step 1:

A mixture of 4-benzyl-2-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane (222mg, 0.69 mmol), 4-isopropoxy-3-methyl-benzoic acid (140 mg, 0.72 mmol)and HATU (262 mg, 0.69 mmol) was stirred in a mixture of DCM (1 mL) andDMF (1 mL) for 5 minutes. Triethylamine (192 μL, 1.38 mmol) was addedand the reaction mixture was stirred for 16 hours, then concentrated invacuo, diluted with sat. aq. NaHCO₃, extracted with ethyl acetate (3×2mL), dried over MgSO₄, filtered and concentrated in vacuo and purifiedby silica gel column chromatography using 0-60% EtOAc/DCM as eluent togive(10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(343 mg, 100%) as a yellow oil. ESI-MS m/z calc. 406.5. found 407.7(M+1)⁺; Retention time: 1.13 minutes (3 min run).

Step 2:

To(10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(264 mg, 0.53 mmol), ammonium formate (167 mg, 2.65 mmol), palladium (30mg, 0.03 mmol) (10% on carbon) was added methanol (5 mL) and thereaction mixture was stirred at 75° C. for 40 minutes. The reactionmixture was cooled, filtered over celite and concentrated in vacuo. Theresidue was partitioned between ethyl acetate and 1:1 sat. aq.NaHCO₃/25% aq. NaOH, dried over MgSO₄, filtered and concentrated invacuo to give(4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone(170 mg, 79%), which was used directly without further purification inthe next step. ESI-MS m/z calc. 408.5. found 409.7 (M+1)⁺; Retentiontime: 1.24 minutes (3 min run).

Preparation of(4-isopropoxy-3-methyl-phenyl)-(8-methyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone

To(4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone(22 mg, 0.05 mmol) in DCM (0.3 mL) was added iodomethane (15 mg, 7 μL,0.11 mmol) followed by the addition of triethylamine (15 μL, 0.11 mmol)and the reaction mixture was stirred for 16 hours at room temperature.The reaction mixture was concentrated in vacuo, diluted with methanol,filtered and purified by prep LCMS (1-99% ACN/H₂O, 5 mM HCl modifier) togive(4-isopropoxy-3-methyl-phenyl)-(10-methyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanonehydrochloride salt as a glassy solid (13 mg, 54%). ESI-MS m/z calc.422.3. found 423.5 (M+1)⁺; Retention time: 1.31 minutes (3 min run).

Preparation of(4-isopropoxy-3-methyl-phenyl)-(8-isopropyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone

To(4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone(30 mg, 0.07 mmol) and acetone (130 μL, 1.77 mmol) in DCE (0.5 mL) wasadded sodium triacetoxyborohydride (50 mg, 0.24 mmol) and the reactionmixture was stirred for 5 hours. The reaction mixture was concentratedin vacuo, diluted with methanol, microfiltered and purified bypreparative LCMS (1-99% ACN/H₂O, 5 mM HCl modifier) to give(4-isopropoxy-3-methyl-phenyl)-(10-isopropyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanonehydrochloride salt (13 mg, 36%) as a glassy solid. ESI-MS m/z calc.450.2. found 451.5 (M+1)⁺; Retention time: 1.38 minutes (3 min run).

Preparation of[8-(2-hydroxy-2-methyl-propyl)-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

(4-Isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone(21 mg, 0.05 mmol) and 2,2-dimethyloxirane (11 mg, 14 μL, 0.15 mmol)were stirred in ethanol (0.3 mL) at 40° C. for 16 hours. The reactionmixture was diluted with methanol, microfiltered, and purified by prepLCMS (10-99% ACN/Water, 5 mM HCl modifier) to give[10-(2-hydroxy-2-methyl-propyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (12 mg, 46%) as a glassy solid. ESI-MS m/z calc.480.3. found 481.7 (M+1)⁺; Retention time: 1.49 minutes (3 min run).

Preparation of[8-(2-hydroxyethyl)-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

(4-Isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone(21 mg, 0.05 mmol), 2-(2-bromoethoxy)tetrahydropyran (13 mg, 9 μL, 0.06mmol) and K₂CO₃ (21 mg, 0.15 mmol) were combined in DMF (0.3 mL) andstirred at 40° C. for 16 hours. The reaction mixture was diluted withether (3 mL), microfiltered and evaporated to give the THP-etherintermediate, which was dissolved in methanol (0.5 mL), then HCl (0.5 mLof 4 M in dioxane, 2.00 mmol) was added and the reaction mixture wasstirred for 30 minutes. The reaction mixture was concentrated in vacuo,diluted with methanol, microfiltered and purified by prep LCMS (10-99%ACN/Water, 5 mM HCl modifier) to give10-(2-hydroxyethyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (10 mg, 40%) as a glassy solid. ESI-MS m/z calc.452.3. found 453.2 (M+1)⁺; Retention time: 1.08 minutes (3 min run).

Preparation of(2-(4-chlorophenyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

Step 1:

To a solution of8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecane (100 mg,0.28 mmol) and 4-isopropoxy-3-methyl-benzoic acid (54 mg, 0.28 mmol) inDMF (1 mL) was added DIEA (98 μL, 0.56 mmol) followed by the addition ofHATU (128 mg, 0.34 mmol). The reaction mixture was stirred for 10minutes, then quenched with water and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was washed with water(twice). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography using 0 to 50% EtOAc/hexanes as eluent to obtain[8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(44 mg, 29%). ESI-MS m/z calc. 532.2. found 533.3 (M+1)⁺; Retentiontime: 2.17 minutes (3 min run).

Step 2:

1-Chloroethyl carbonochloridate (142 mg, 108 μL, 0.99 mmol) was added toa solution of[8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(44 mg, 0.08 mmol) in DCE (508 μL) at room temperature and then thereaction mixture was heated at reflux for 1 hour. The excess solvent wasremoved in vacuo and the carbamate intermediate was dissolved in MeOH (2mL) and heated at reflux for 20 minutes. The reaction mixture was cooledto room temperature, filtered and purified by Waters mass directedLC/MS-HPLC: (1-99% ACN/H₂O (5 mM HCl)). The desired fractions wereconcentrated to dryness, dissolved in EtOAc and washed with 1M NaOH. Thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo to yield[10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(22 mg, 60%). ESI-MS m/z calc. 442.2. found 443.5 (M+1)⁺; Retentiontime: 1.51 minutes (3 min run).

Step 3:

2,2-difluoroethyl trifluoromethanesulfonate (17 mg, 0.08 mmol) was addedto a solution of[10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(22 mg, 0.05 mmol) and NaHCO₃ (13 mg, 0.15 mmol) in anhydrous ethanol(0.3 mL) at room temperature. The reaction mixture was purged withargon, sealed with a cap and heated at 70° C. for 40 minutes. Thereaction mixture was cooled to room temperature, diluted with MeOH to 1mL, microfiltered and purified by Waters mass directed LC/MS: (10-99%ACN/H₂O (5 mM HCl)) to yield[10-(4-chlorophenyl)-8-(2,2-difluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(27 mg, 100%). ESI-MS m/z calc. 506.21478. found 507.2 (M+1)⁺; Retentiontime: 2.17 minutes (3 min run).

Preparation of(2-(2-chlorophenyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(3-fluoro-4-isopropoxyphenyl)methanone

This compound was prepared following the above procedure, using8-benzyl-10-(2-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecane in step1 and using 3-fluoro-4-isopropoxy-benzoic acid as the acid reagent instep 3. ESI-MS m/z calc. 510.2. found 511.5 (M+1)⁺; Retention time: 2.25minutes. ¹H NMR (400 MHz, DMSO) δ 7.61 (dd, J=7.8, 1.2 Hz, 1H),7.50-7.31 (m, 3H), 7.30-7.12 (m, 3H), 6.36-6.00 (m, 1H), 5.08 (d, J=13.4Hz, 1H), 4.74-4.64 (m, 1H), 4.12-3.91 (m, 1H), 3.73-3.59 (m, 2H), 3.32(dd, J=32.0, 10.6 Hz, 1H), 3.06 (dd, J=11.0, 3.1 Hz, 1H), 2.91 (dd,J=11.6, 2.6 Hz, 1H), 2.86-2.65 (m, 2H), 2.44-2.30 (m, 1H), 2.19 (d,J=9.6 Hz, 1H), 2.13-1.99 (m, 1H), 1.70-1.55 (m, 3H), 1.30 (d, J=6.0 Hz,6H).

Preparation of(4-(2,2-difluoroethyl)-2-(p-tolyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

Step 1:

A mixture of 8-benzyl-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecane(100 mg, 0.30 mmol), 4-isopropoxy-3-methyl-benzoic acid (61 mg, 0.31mmol) and HATU (119 mg, 0.31 mmol) was stirred in DCM (450 μL) and DMF(450 μL) for 5 minutes. Triethylamine (83 μL, 0.59 mmol) was added andthe reaction mixture was stirred overnight. The reaction mixture wasdiluted with sat. aq. NaHCO₃ (5 mL) and extracted with DCM (3×5 mL),dried over MgSO₄, filtered, concentrated in vacuo and purified by silicagel column chromatography (0-100% EtOAc/hexane) to give[8-benzyl-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanoneas a colorless oil (120 mg, 79%). ESI-MS m/z calc. 512.3. found 513.3(M+1)⁺; Retention time: 1.86 minutes (3 min run).

Step 2:

To[8-benzyl-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(120 mg, 0.23 mmol) in ethanol (1.2 mL) was added ammonium formate (69mg, 1.09 mmol) and Pd(OH)₂ (18 mg, 0.025 mmol) and the reaction mixturewas heated at 75° C. for 60 minutes. The reaction mixture was cooled,filtered, concentrated in vacuo and the residue was dissolved with ethylacetate (10 mL) and washed with sat. aq. NaHCO₃ (5 mL). The aqueouslayer was extracted further with ethyl acetate (2×10 mL). The combinedorganics were dried over MgSO₄, filtered and concentrated in vacuo togive the amine intermediate. The amine intermediate was dissolved inethanol (600 μL) and NaHCO₃ (79 mg, 0.94 mmol) and 2,2-difluoroethyltrifluoromethanesulfonate (74 mg, 0.35 mmol) were added. The reactionmixture was heated at 40° C. overnight, filtered and then purified bypreparative LCMS (10-99% ACN/water, HCl modifier as modifier) to give[8-(2,2-difluoroethyl)-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone.ESI-MS m/z calc. 486.3. found 487.3 (M+1)⁺; Retention time: 2.39 minutes(3 min run).

Preparation of(4-benzyl-2-(5-methyloxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

Step 1:

To tert-butyl8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4 mL of 4 M in dioxane,16.11 mmol) and the mixture was stirred for 30 minutes. The reactionmixture was concentrated in vacuo, then DMF (4 mL),4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) anddimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammoniumhexafluorophosphate (613 mg, 1.61 mmol) were added and the reactionmixture was stirred for 10 minutes. Triethylamine (898 μL, 6.44 mmol)was added and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated in vacuo, dilutedwith DCM (5 mL), washed with 1 N aq. NaOH (2 mL) and brine (2 mL), driedover MgSO₄ and concentrated in vacuo. The residue was purified by silicagel column chromatography using 0-100% EtOAc/hexane as eluent to give(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanoneas a pale yellow oil (715 mg, 99%). ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.22(m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H),5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14(m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz,1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0Hz, 6H); ESI-MS m/z calc. 448.6. found 449.5 (M+1)⁺; Retention time:1.54 minutes (3 min run).

Step 2:

To(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(2.4 g, 5.6 mmol) and 4-methylmorpholine 4-oxide (698 mg, 5.96 mmol) inacetone (22 mL) and water (2.5 mL) was added osmium tetroxide (677 μL of2.5% w/w, 0.05 mmol) dropwise and the reaction mixture was stirred for 2hours. The reaction mixture was quenched with 1M sodium thiosulfate (100mL) and stirred for 5 minutes, then extracted with EtOAc (4×100 mL),washed with sat. aq. sodium bicarbonate (100 mL) and dried over MgSO₄and concentrated in vacuo to give the diol intermediate (˜2.5 g). Thereaction mixture was purified by basic alumina column chromatographyusing 0-20% MeOH/DCM as eluent to obtain[8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(2.18 g, 84%). ESI-MS m/z calc. 482.6. found 483.7 (M+1)⁺; Retentiontime: 1.10 minutes (3 min run).

Step 3:

To[8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(1.53 g, 3.17 mmol) in THF (28 mL) was added NaIO₄ (1.36 g, 6.34 mmol)followed by the addition of water (10 mL). The reaction mixture wasstirred at room temperature for 2 hours, then filtered through celite,and concentrated in vacuo. The residue was partitioned between sat. aq.sodium bicarbonate (50 mL) and ethyl acetate (50 mL) and the aqueouslayer was extracted further with ethyl acetate (3×50 mL). The organicswere combined, washed with sat. aq. sodium bicarbonate (50 mL), driedover MgSO₄, and concentrated in vacuo. To the intermediate aldehyde(˜1.4 g) was added 2-methylpropan-2-ol (17 mL) and 2-methylbut-2-ene (9mL, 85.08 mmol) and the reaction mixture was cooled to 0° C. A solutionof NaClO₂ (938 mg, 8.29 mmol) and NaH₂PO₄ (1.15 g, 8.31 mmol) in water(17 mL) was added dropwise over 5 minutes, and the reaction mixture wasstirred for 30 minutes. The reaction mixture was warmed to roomtemperature, then extracted with ethyl acetate (4×50 mL) and thecombined organic layer was washed with brine (15 mL), dried over MgSO₄,filtered and concentrated in vacuo to give8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylicacid as a white foam (1.48 g, 100%). ESI-MS m/z calc. 466.6. found 467.5(M+1)⁺; Retention time: 1.27 minutes (3 min run).

Step 4:

To8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylicacid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P(641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL)and the reaction mixture was then heated at 75° C. for 2 hours. Thereaction mixture was cooled to room temperature and partitioned betweenEtOAc/saturated aq. NaHCO₃. The layers were separated and the aqueouslayer was extracted with EtOAc (2×). The combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo to a dark foam. Thecrude product was purified by silica gel column chromatography using20-70% EtOAC in DCM as eluent to affordN-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide(92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. found 522.5(M+1)⁺; Retention time: 1.48 minutes (3 min run).

Step 5:

ToN-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide(136 mg, 0.26 mmol) in THF (3 mL) was added Burgess' Salt (155 mg, 0.65mmol) and the reaction mixture was heated at 75° C. in a sealed vial for2 hours. The solvents were removed under reduced pressure, and theresidue was dissolved in DMF (1 mL), filtered and purified by Waterspreparative LC/MS (1-99% ACN/H₂O (5 mM HCl)). The desired fractions wereconcentrated in vacuo and the residue partitioned betweenEtOAc/saturated aqueous NaHCO₃ solution. The layers were separated andthe aqueous layer was extracted with EtOAc (2×). The combined organicswere dried over Na₂SO₄, filtered and concentrated in vacuo to yield8-benzyl-10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(76 mg, 58%) as a foam. ESI-MS m/z calc. 503.6. found 504.5 (M+1)⁺;Retention time: 1.74 minutes (3 min run).

Preparation of(4-isopropoxy-3-methylphenyl)(2-(5-methyloxazol-2-yl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methanone

Step 1:

A mixture of8-benzyl-10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanone(46 mg, 0.09 mmol), palladium, 10 wt. % on activated carbon (19 mg, 0.18mmol) and ammonium formate (35 mg, 0.55 mmol) in EtOH (750 μL) washeated to 65° C. for 50 minutes. The reaction mixture was cooled to roomtemperature, microfiltered and 80% of the solvent was removed in vacuoand then diluted with DMF (1 mL) and purified by Waters prep LC/MS(1-99% ACN/H₂O (5 mM HCl)) to yield(4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanonehydrochloride salt (32 mg, 78%). ESI-MS m/z calc. 413.2. found 414.7(M+1)⁺; Retention time: 0.99 minutes (3 min run).

Step 2:

A mixture of(4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanonehydrochloride salt (32 mg, 0.07 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (17 μL, 0.11 mmol) and NaHCO₃ (24 mg, 0.28mmol) in anhydrous EtOH (800 μL) was heated at 80° C. in a sealed vialfor 18 hours. The reaction mixture was allowed to cool to roomtemperature, microfiltered and purified by Waters mass directed LC/MS:(10-99% ACN/H₂O (5 mM HCl)) and concentrated in vacuo to yield(4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(3 mg, 9%) as a white solid. ESI-MS m/z calc. 495.5. found 496.7 (M+1)⁺;Retention time: 1.99 minutes (3 min run); ¹H NMR (400 MHz, DMSO) δ7.27-7.13 (m, 2H), 6.96 (d, J=9.0 Hz, 1H), 6.82 (d, J=1.2 Hz, 1H), 4.86(dd, J=12.0, 4.7 Hz, 1H), 4.71-4.54 (m, 1H), 3.32-3.14 (m, 5H), 3.07(dd, J=11.5, 2.6 Hz, 1H), 2.90-2.83 (m, 1H), 2.70 (dd, J=18.3, 7.2 Hz,1H), 2.41-2.23 (m, 6H), 2.13 (s, 3H), 1.64-1.39 (m, 3H), 1.29 (d, J=6.0Hz, 6H).

Preparation of[8-(2,2-difluoroethyl)-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

To a solution of[8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(417 mg, 0.86 mmol) in THF (10 mL) was added NaIO₄ (468 mg, 2.19 mmol)and H₂O (4 mL). The reaction mixture was stirred at room temperature for2 hours. The reaction mixture was filtered and partitioned between sat.aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extractedfurther with ethyl acetate (3×50 mL). The organics were combined, washedwith sat. aq. sodium bicarbonate (50 mL), dried over MgSO₄, filtered andconcentrated in vacuo to yield8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carbaldehyde(384 mg, 99%) as a white solid. ESI-MS m/z calc. 450.3. found 451.3(M+1)⁺; Retention time: 1.33 minutes (3 min run).

Step 2:

Oxaldehyde (543.1 μL of 40% w/w, 4.75 mmol) was added to a solution of8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carbaldehyde(306 mg, 0.68 mmol) and ammonium hydroxide (881.4 μL of 30% w/w, 6.79mmol) in MeOH (3 mL) and the reaction mixture was stirred at roomtemperature. After 3 hours, an additional 0.5 eq of oxaldehyde and 1.0eq. of ammonium hydroxide were added and the reaction mixture wasstirred for an additional 14 hours. The reaction mixture was partitionedbetween EtOAc and saturated aqueous NaHCO₃, the layers were separatedand the aqueous layer was extracted once more with EtOAc. The combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo togive a dark oil. The residue was purified by silica gel columnchromatography using 0-5% MeOH in DCM to yield[8-benzyl-10-(1H-imidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(236 mg, 71%) as a yellow solid. ESI-MS m/z calc. 488.3. found 489.5(M+1)⁺; Retention time: 1.45 minutes (3 min run).

Step 3:

[8-Benzyl-10-(1H-imidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(233 mg, 0.48 mmol) was suspended in a mixture of anhydrous DMF (1.5mL)/THF (0.1 mL) under an atmosphere of nitrogen at 0° C. NaH (19 mg,0.48 mmol) was added and the reaction mixture was stirred for 30minutes, then MeI (68 mg, 30 μL, 0.48 mmol) was added and the reactionmixture was stirred for 10 minutes. The reaction mixture was quenchedwith water and diluted with EtOAc, the layers were separated and theaqueous layer was extracted once more with EtOAc. The combined organicswere washed with brine solution (2×5 mL), dried over Na₂SO₄, filteredand concentrated in vacuo to an oil. The residue was purified by silicagel column chromatography using 0-5% MeOH in DCM to yield[8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(205 mg, 86%) as a white foam. ESI-MS m/z calc. 502.3. found 503.1(M+1)⁺; Retention time: 1.51 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 7.38-7.30 (m, 4H), 7.25 (ddd, J=8.4, 5.9, 2.2 Hz, 1H), 7.19 (d, J=7.0Hz, 2H), 7.10 (d, J=1.1 Hz, 1H), 6.96 (t, J=5.9 Hz, 1H), 6.75 (d, J=1.1Hz, 1H), 4.96 (ddd, J=9.9, 6.7, 2.4 Hz, 1H), 4.68-4.59 (m, 1H), 3.70 (s,3H), 3.53 (td, J=13.6, 9.0 Hz, 3H), 3.30-3.15 (m, 2H), 2.93 (dd, J=11.1,0.7 Hz, 1H), 2.74-2.69 (m, 1H), 2.66-2.52 (m, 2H), 2.13 (s, 3H),1.95-1.86 (m, 1H), 1.61-1.33 (m, 4H), 1.28 (d, J=6.9 Hz, 6H).

Step 4:

To a solution of[8-benzyl-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(50 mg, 0.10 mmol) in EtOH (500 μL) was added Pd(OH)₂ (6.98 mg, 0.01mmol) and ammonium formate (29 mg, 0.46 mmol) and the reaction mixturewas heated at 65° C. for 1.5 hours. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate, filtered and washed withsat. aq. NaHCO₃ (pH 10)/brine. The aqueous was extracted further withethyl acetate. The combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo to give(4-isopropoxy-3-methyl-phenyl)-[10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(38 mg, 94%) as a clear colorless oil. ESI-MS m/z calc. 412.2. found413.3 (M+1)⁺; Retention time: 1.16 minutes (3 min run).

Step 5:

2,2-Difluoroethyl trifluoromethanesulfonate (24 mg, 0.11 mmol) was addedto a mixture of(4-isopropoxy-3-methyl-phenyl)-[10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(38 mg, 0.09 mmol) and NaHCO₃ (23 mg, 0.28 mmol) in EtOH (0.3 mL). Thereaction mixture was purged with argon, sealed and heated at 50° C. for1 hour. The reaction mixture was cooled to room temperature, dilutedwith DMF (1 mL), and microfiltered. The residue was purified by Watersmass directed LC/MS: (1-99% ACN/H₂O (5 mM HCl)) to yield[8-(2,2-difluoroethyl)-10-(1-methylimidazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (28 mg, 58%). ESI-MS m/z calc. 476.3. found 477.3(M+1)⁺; Retention time: 1.5 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 7.74 (d, J=1.9 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.18 (dd, J=6.0, 2.0Hz, 2H), 7.04-6.90 (m, 1H), 6.20 (tt, J=55.5, 4.0 Hz, 1H), 5.34-5.28 (m,1H), 4.69-4.57 (m, 1H), 3.91 (s, 3H), 3.69-3.41 (m, 1H), 3.37-3.09 (m,3H), 2.87 (ddd, J=19.6, 18.4, 7.9 Hz, 3H), 2.57-2.51 (m, 2H), 2.46-2.31(m, 1H), 2.26 (d, J=11.6 Hz, 1H), 2.13 (s, 3H), 1.70-1.52 (m, 3H), 1.29(d, J=6.0 Hz, 6H).

Preparation of8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanoneand8-(2,2-difluoroethyl)-10-(2-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

To8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane(193 mg, 0.54 mmol), 4-isopropoxy-3-methyl-benzoic acid (110 mg, 0.56mmol) and HATU (215 mg, 0.56 mmol) was added N,N-dimethylformamide (1.3mL). The reaction mixture was stirred for 5 minutes at room temperature,then diisopropylethylamine (374 μL, 2.15 mmol) was added and thereaction mixture was stirred overnight. The reaction mixture was thendiluted with sat. NaHCO₃ (5 mL) and the aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic layer was washed withwater (5 mL), dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was passed through a silica gel plug, eluting with 30%EtOAc/DCM. The solvent was concentrated in vacuo and the residue wasdissolved in N,N-dimethylformamide (1.3 mL) under an atmosphere ofnitrogen, cooled to 0° C., then treated with NaH (21 mg, 0.54 mmol). Thereaction mixture was stirred at 0° C. for 10 minutes, then at roomtemperature for 5 minutes, then iodoethane (50 μL, 0.63 mmol) was addedand the reaction mixture stirred for 1 hour. The reaction mixture wasdiluted with methanol, microfiltered and purified by preparative LCMS(10-99% ACN/Water, 5 mM HCl modifier) to give8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(26 mg, 14%) and8-(2,2-difluoroethyl)-10-(2-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(24 mg, 13%).

Data for8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanone:ESI-MS m/z calc. 490.3. found 491.3 (M+1)⁺; Retention time: 1.89 minutes(3 min run); ¹H NMR (400 MHz, CD₃CN) δ 7.54 (d, J=2.3 Hz, 1H), 7.20-7.17(m, 2H), 7.00-6.71 (m, 1H), 6.92 (d, J=9.0 Hz, 1H), 6.34 (d, J=2.3 Hz,1H), 5.26 (d, J=10.2 Hz, 1H), 4.66-4.60 (m, 1H), 4.14 (q, J=7.3 Hz, 2H),3.63-3.35 (m, 5H), 3.37-3.13 (m, 3H), 3.08 (d, J=13.2 Hz, 1H), 2.95 (d,J=12.6 Hz, 1H), 2.18 (s, 3H), 1.75-1.55 (m, 4H), 1.41 (t, J=8 Hz, 3H),1.32 (d, J=6.0 Hz, 6H).

Data for8-(2,2-difluoroethyl)-10-(2-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanone:ESI-MS m/z calc. 490.3. found 491.5 (M+1)⁺; Retention time: 1.82 minutes(3 min run); ¹H NMR (400 MHz, CD₃CN) δ 7.45 (s, 1H), 7.22-7.20 (m, 2H),6.94 (d, J=8 Hz, 1H), 6.63-6.34 (m, 1H), 6.34 (s, 1H), 6.29 (s, 1H),5.29 (d, J=8.6 Hz, 1H), 4.74-4.54 (m, 1H), 4.24 (q, J=7.0 Hz, 2H),3.40-3.09 (m, 6H), 3.05-2.59 (m, 3H), 2.20 (s, 3H), 1.89-1.50 (m, 4H),1.43 (t, J=8 Hz, 3H), 1.34 (d, J=6 Hz, 6H).

Preparation of tert-butyl8-(2,2-difluoroethyl)-10-(1-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateand tert-butyl8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate

A solution tert-butyl8-(2,2-difluoroethyl)-10-prop-2-ynoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(40 mg, 0.11 mmol), hydrazine (69 mg, 67 μL, 2.15 mmol) and ethanol (800μL) was stirred for one hour at room temperature. The reaction mixturewas concentrated in vacuo, diluted with 1:1 of 1M aq. NaOH/sat. aq.NaHCO₃ (2 mL), and extracted with DCM (3×3 mL). The combined organicswere dried over MgSO₄, filtered and concentrated in vacuo to give thepyrazole intermediate, which was dissolved in N,N-dimethylformamide (0.5mL) and NaH (8 mg, 0.20 mmol) was added. The reaction mixture wasstirred for 20 minutes at room temperature, then iodomethane (30 mg, 13μL, 0.21 mmol) was added and the reaction mixture was stirred for 2hours. The reaction mixture was concentrated in vacuo and the residuewas purified by silica gel column chromatography using 0-100% EtOAc/DCMas eluent to give tert-butyl8-(2,2-difluoroethyl)-10-(1-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateand tert-butyl8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateas a colorless foam in a 1:1 mixture (36 mg, 84%). ESI-MS m/z calc.400.2. found 401.5 (M+1)⁺; Retention time: 1.63 and 1.71 minutes (3 minrun); ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.21 (m, 1H), 6.17-6.10 (m, 1H),5.95-5.64 (m, 1H), 4.85-4.78 (m, 1H), 3.89-3.79 (m, 3H), 3.74-3.48 (m,2H), 3.28-3.04 (m, 2H), 2.99-2.94 (m, 1H), 2.75-2.60 (m, 3H), 2.50-2.32(m, 2H), 1.60-1.41 (m, 4H), 1.39-1.37 (m, 9H).

Preparation of8-(2,2-difluoroethyl)-10-(1-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanoneand8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

The mixture of regioisomeric pyrazoles, tert-butyl8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateand tert-butyl8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(31 mg, 0.08 mmol) was dissolved in ethanol (100 μL) and HCl (193.5 μLof 4 M in dioxane, 0.77 mmol) was added. The reaction mixture wasstirred for 2 hours at room temperature, and then concentrated in vacuo.4-Isopropoxy-3-methyl-benzoic acid (15.04 mg, 0.08 mmol), HATU (29 mg,0.08 mmol) and N,N-dimethylformamide (484 μL) were added, followed bythe addition of diisopropylethylamine (54 μL, 0.31 mmol). The reactionmixture was stirred for 2 hours at room temperature, then diluted withmethanol, microfiltered and purified by preparative LCMS (10-99%ACN/Water, 5 mM HCl modifier) to give the title compounds as whitesolids.

Data for8-(2,2-difluoroethyl)-10-(1-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanone:ESI-MS m/z calc. 476.3. found 477.3 (M+1)⁺; Retention time: 1.77 minutes(3 min run); ¹H NMR (400 MHz, CD₃CN) δ 7.50 (d, J=2.3 Hz, 1H), 7.21-7.17(m, 2H), 7.00-6.69 (m, 1H), 6.92 (d, J=9.1 Hz, 1H), 6.35 (d, J=2.3 Hz,1H), 5.26 (d, J=9.6 Hz, 1H), 4.66-4.60 (m, 1H), 3.85 (s, 3H), 3.67-3.37(m, 5H), 3.36-3.01 (m, 4H), 2.95 (d, J=12.7 Hz, 1H), 2.18 (s, 3H),1.81-1.51 (m, 4H), 1.32 (t, J=5.4 Hz, 6H).

Data for8-(2,2-difluoroethyl)-10-(2-methylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl-(4-isopropoxy-3-methyl-phenyl)methanone:¹H NMR (400 MHz, CD₃CN) δ 7.39 (d, J=1.9 Hz, 1H), 7.24-7.19 (m, 2H),6.92 (d, J=9.0 Hz, 1H), 6.72-6.39 (m, 1H), 6.28 (d, J=1.9 Hz, 1H),5.32-5.26 (m, 1H), 4.70-4.61 (m, 1H), 3.90 (s, 3H), 3.49-3.19 (m, 6H),3.05-2.69 (m, 4H), 2.21 (s, 3H), 1.85-1.54 (m, 4H), 1.30 (t, J=10.1 Hz,6H); ESI-MS m/z calc. 476.3. found 477.4 (M+1)⁺; Retention time: 6.04minutes (15 min run).

(4-(2,2-Difluoroethyl)-2-(1-methyl-1H-pyrazol-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(3-fluoro-4-isopropoxyphenyl)methanonewas prepared using the procedure as described above, using3-fluoro-4-isopropoxy-benzoic acid as the acid reagent.

Preparation of8-(2,2-difluoroethyl)-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone

Step 1:

To a solution of tert-butyl8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(500 mg, 1.11 mmol) in DCM (1 mL) was added HCl (3 mL of 4 M in dioxane,11.05 mmol) dropwise. The reaction mixture was stirred overnight at roomtemperature. The solvent was concentrated in vacuo and the residue wasdissolved in the minimum amount of DCM and precipitated with ether. Thesolvent was decanted and the residue was again washed with ether anddried to give8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane(400 mg, 93%). ESI-MS m/z calc. 352.2. found 353.7 (M+1)⁺; Retentiontime: 0.99 minutes (3 min run).

Step 2:

To a solution of8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane(400 mg, 1.03 mmol) in DMF (2 mL) was added DIEA (266 mg, 358 μL, 2.06mmol) followed by the addition of 4-isopropoxy-3-methoxy-benzoic acid(238 mg, 1.13 mmol) and HATU (469 mg, 1.23 mmol). The reaction mixturewas stirred for 10 minutes at room temperature. The reaction mixture wasquenched with water and the aqueous layer was extracted with ethylacetate. The organic layer was washed with water (3×10 mL), dried overMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by silica gel column chromatography using 0 to 60% EtOAc inhexanes as eluent to obtain(4-isopropoxy-3-methoxy-phenyl)-[8-(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-ylmethanone(300 mg, 54%). ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.18 (m, 7H), 6.97-6.78(m, 5H), 4.94-4.71 (m, 1H), 4.59-4.50 (m, 1H), 4.33-4.17 (m, 1H), 3.83(d, J=13.0 Hz, 6H), 3.69-3.39 (m, 3H), 3.32 (d, J=13.0 Hz, 1H),3.02-2.89 (m, 1H), 2.80 (s, 2H), 2.69-2.48 (m, 2H), 2.09-1.85 (m, 2H),1.37 (d, J=6.1 Hz, 6H), 1.29-1.14 (m, 1H), 0.95-0.79 (m, 1H); ESI-MS m/zcalc. 544.7. found 545.3 (M+1)⁺; Retention time: 1.58 minutes (3 minrun).

Step 3:

To(4-isopropoxy-3-methoxy-phenyl)-[8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(175 mg, 0.32 mmol), Pd(OH)₂ (129 mg, 0.9186 mmol) and ammonium formate(405 mg, 6.43 mmol) was added ethanol. The reaction mixture was thenheated at 65° C. for 16 hours. The reaction mixture was filtered, thesolvent evaporated and the residue was purified by silica gel columnchromatography using 0 to 60% EtOAc in hexanes as eluent to give(4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone.ESI-MS m/z calc. 424.5. found 425.5 (M+1)¹; Retention time: 1.28 minutes(3 min run).

Step 4:

To a solution of(4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone(15 mg, 0.04 mmol) in ethanol (375 μL) was added NaHCO₃ (12 mg, 0.14mmol), followed by the addition of 2,2-difluoroethyltrifluoromethanesulfonate (11 mg, 0.05 mmol). The reaction mixture washeated at 80° C. for 16 hours. The reaction mixture was filtered andpurified by Waters mass directed LC/MS: (1-99% ACN/H₂O (5 mM HCl) toobtain[8-(2,2-difluoroethyl)-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone(5 mg, 29%). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.36 (m, 5H), 6.98-6.83 (m,3H), 5.25 (d, J=10.4 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 3.85 (s,3H), 3.60 (d, J=10.9 Hz, 1H), 3.47-3.12 (m, 6H), 2.86-2.60 (m, 3H),1.88-1.50 (m, 5H), 1.38 (d, J=6.1 Hz, 6H); ESI-MS m/z calc. 488.5. found489.7 (M+1)⁺; Retention time: 2.17 minutes (3 min run).

(4-Isopropoxy-3-methoxy-phenyl)-[9-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanonewas prepared using the chemistry described above using2,2,2-trifluoroethyl trifluoromethanesulfonate in step 4. ESI-MS m/zcalc. 506.6. found 507.5 (M+1)⁺; Retention time: 2.27 minutes (3 minrun).

Preparation of[10-ethyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

To tert-butyl8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4.028 mL of 4 M indioxane, 16.11 mmol) and the reaction mixture was stirred for 30minutes. The reaction mixture was concentrated in vacuo, then DMF (4mL), 4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) and HATU(613 mg, 1.61 mmol) were added and the reaction mixture was stirred for10 minutes. Triethylamine (898 μL, 6.44 mmol) was added and the reactionmixture was stirred for 16 hours, The reaction mixture was concentratedin vacuo, diluted with DCM (5 mL), washed with 1 N aq. NaOH (2 mL) andbrine (2 mL), dried over MgSO₄, filtered and concentrated in vacuo. Thecrude material was purified by silica gel column chromatography using0-100% EtOAc/hexanes eluent to give(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(715 mg, 99%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.22(m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H),5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14(m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz,1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0Hz, 6H); ESI-MS m/z calc. 448.6. found 449.5 (M+1)⁺; Retention time:1.48 minutes (3 min run).

Step 2:

To(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(150 mg, 0.33 mmol), ammonium formate (74 mg, 1.17 mmol) and Pd (17 mg,0.02 mmol) (10% on activated carbon) was added methanol (2 mL) and thereaction mixture was heated at 75° C. for 30 minutes. The reactionmixture was cooled, microfiltered and concentrated in vacuo, thendiluted with DCM (20 mL), washed with aq. 1M NaOH (10 mL), extractedwith DCM (120 mL), washed with brine (10 mL), dried over MgSO₄ andconcentrated in vacuo to give(10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(100 mg, 83%) as a colorless oil. ESI-MS m/z calc. 360.5. found 361.3(M+1)⁺; Retention time: 1.25 minutes (3 min run).

Step 3:

To(10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(33 mg, 0.09 mmol) in ethanol (0.5 mL) was added NaHCO₃ (15 mg, 0.18mmol) then iodoethane (21 mg, 11 μL, 0.14 mmol). The reaction mixturewas heated at 50° C. for 16 hours, then microfiltered and purified byprep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give(8,10-diethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (39 mg, 100%); ESI-MS m/z calc. 388.3. found 389.7(M+1)⁺; Retention time: 1.36 (3 min run).

[10-ethyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonewas also prepared using the procedure above using 2,2,2-trifluoroethyltrifluoromethanesulfonate in step 3. ESI-MS m/z calc. 442.2. found 443.7(M+1)⁺; Retention time: 2.33 (3 min run).

Preparation of(8-benzyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone

A mixture of(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(50 mg, 0.11 mmol) and Pd (4 mg, 0.003 mmol) (10% on activated carbon)in methanol (1 mL) was stirred under an atmosphere of hydrogen for 2hours. The reaction mixture was microfiltered and purified by prep LCMS(10-99% ACN/Water, 5 mM HCl modifier) to give(8-benzyl-10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (8 mg, 15%) as a white solid. ESI-MS m/z calc. 450.3.found 451.5 (M+1)⁺; Retention time: 1.36 minutes (3 min run).

Preparation of[8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

To(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(135 mg, 0.30 mmol) in DCM (4 mL) and methanol (1 mL) at −78° C. wasbubbled ozone until the solution turned faint blue. NaBH₄ (91 mg, 2.41mmol) and methanol (˜2 mL) was added under an atmosphere of nitrogen andthe reaction mixture was stirred at −78° C. for 30 minutes, then at 0°C. for 1 hour. The reaction mixture was concentrated in vacuo, quenchedwith 4N HCl/dioxane, concentrated in vacuo, then diluted withmethanol-water (1:1), microfiltered and purified by prep LCMS (1-99%ACN/Water, 5 mM HCl modifier) to give[8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(50 mg, 34%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)⁺; Retentiontime: 1.18 minutes (3 min run).

Preparation of[10-(ethoxymethyl)-8-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

To[8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (43 mg, 0.09 mmol) in DMF (0.5 mL) was added sodiumhydride (11 mg, 0.30 mmol) and the reaction mixture was stirred for 20minutes. Iodoethane (30 μL, 0.38 mmol) was added and the reactionmixture was stirred for 3 hours, then diluted with EtOAc, filtered,concentrated in vacuo. The residue was purified by silica gel columnchromatography using 10-100 EtOAc/hexanes eluent to give the etherintermediate as pale yellow oil. The oil was dissolved in methanol (0.6mL), and Pd (5 mg, 0.004 mmol) and ammonium formate (27 mg, 0.44 mmol)were added and the reaction mixture was heated at 75° C. for 40 minutes.The reaction mixture was filtered, concentrated in vacuo, diluted withethyl acetate, washed with 1:1 3M NaOH/sat. aq. NaHCO₃, dried overMgSO₄, filtered and concentrated in vacuo to give[10-(ethoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(25 mg, 74%) as a pale yellow oil. ESI-MS m/z calc. 390.5. found 391.3(M+1)⁺; Retention time: 1.17 minutes (3 min run).

Step 2:

To[10-(ethoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(25 mg, 0.06 mmol) and NaHCO₃ (16 mg, 0.19 mmol) in ethanol (0.5 mL) wasadded iodoethane (15 mg, 8 μL, 0.10 mmol) and the reaction mixture washeated in a sealed vial at 70° C. for 24 hours. The reaction mixture wasmicrofiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HClmodifier) to give[10-(ethoxymethyl)-8-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (19 mg, 66%) as a colorless oil. ESI-MS m/z calc.418.3. found 419.7 (M+1)+; Retention time: 1.20 minutes (3 min run).

Preparation of[8-benzyl-10-(1-hydroxy-1-methyl-ethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

8-Benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylicacid (10 mg, 0.02 mmol), K₂CO₃ (12 mg, 0.09 mmol) and iodomethane (2 μL,0.03 mmol) in DMF (0.1 mL) was stirred for 1 hour. The mixture wasdiluted with ethyl acetate (5 mL), washed with water (2 mL) and brine (2mL), dried over magnesium sulfate, filtered and evaporated to givemethyl8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylate(10 mg, 100%). ESI-MS m/z calc. 480.6. found 481.5 (M+1)⁺; Retentiontime: 1.82 minutes (3 min run).

Step 2:

To methyl8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylate(100 mg, 0.21 mmol) in THF (0.5 mL) at −78° C. was addedchloro(methyl)magnesium (150 μL of 3 M in THF, 0.45 mmol) and thereaction mixture was stirred for 2 hours then allowed to warm to roomtemperature. The reaction mixture was diluted with water, extracted withethyl acetate and dried over MgSO₄, then purified by silica gel columnchromatography using 0-100% EtOAc/DCM as eluent to give[8-benzyl-10-(1-hydroxy-1-methyl-ethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(81 mg, 80%) as a white foam. ESI-MS m/z calc. 480.6. found 481.7(M+1)⁺; Retention time: 1.22 minutes (3 min run).

Preparation of[10-(1-hydroxy-1-methyl-ethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

[8-Benzyl-10-(1-hydroxy-1-methyl-ethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(75 mg, 0.16 mmol) was dissolved in ethanol (3 mL) and Pd (8 mg, 0.008mmol) and ammonium formate (50 mg, 0.80 mmol) were added and thereaction mixture was heated at 75° C. for 30 minutes. The reactionmixture was filtered, concentrated in vacuo, diluted with ethyl acetate,washed with 3M NaOH, dried over MgSO₄, filtered and concentrated invacuo to give(2-(2-hydroxypropan-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone(60 mg, 94%). ESI-MS m/z calc. 390.3. found 391.5 (M+1)⁺; Retentiontime: 1.27 minutes (3 min run).

Step 2:

(2-(2-Hydroxypropan-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone(25 mg, 0.06 mmol) was dissolved in dry ethanol (300 μL) and NaHCO₃ (50mg, 0.60 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (20μL, 0.13 mmol) were added and the reaction mixture was heated at 80° C.for 16 hours. The reaction mixture was filtered, concentrated in vacuoand purified by silica gel column chromatography using 0-100%EtOAc/hexanes as eluent to give[10-(1-hydroxy-1-methyl-ethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(15 mg, 53%) as a colorless oil. ESI-MS m/z calc. 472.5. found 473.5(M+1)⁺; Retention time: 1.93 minutes (3 min run).

Preparation of[8-benzyl-10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

To(8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(95 mg, 0.21 mmol) and chloro-tris(triphenylphosphoranyl)rhodium (6 mg,0.006 mmol) in THF (1 mL) was added catecholborane (635 μL of 1 M inTHF, 0.64 mmol) at 0° C. and the reaction mixture was stirred at roomtemperature for 1 hour. Sodium hydroxide (0.3 mL of 3 M, 0.90 mmol) wasadded slowly, followed by the addition of H₂O₂ (0.3 mL of 30% w/w, 2.94mmol) and the reaction mixture was stirred for 15 minutes. The reactionmixture was extracted three times with ethyl acetate and the combinedorganics were concentrated in vacuo and purified by prep LCMS (1-99%ACN/Water, 5 mM HCl modifier) to give[8-benzyl-10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (55 mg, 50%) as a pale yellow solid. ESI-MS m/z calc.466.3. found 467.3 (M+1)⁺; Retention time: 1.01 minutes (3 min run).

Preparation of[10-(2-hydroxyethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone

Step 1:

To a solution of[8-benzyl-10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (40 mg, 0.08 mmol) in methanol (750 μL) was added Pd(4 mg, 0.004 mmol) and ammonium formate (25 mg, 0.39 mmol), and thereaction mixture was heated at 75° C. for 1 hour. The reaction mixturewas microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HClmodifier) to give[10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (20 mg, 62%). ESI-MS m/z calc. 376.2. found 377.3(M+1)⁺; Retention time: 1.01 minutes (3 min run).

Step 2:

To[10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride salt (20 mg, 0.05 mmol) and NaHCO₃ (16 mg, 0.19 mmol) inethanol (0.5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (11 μL, 0.07 mmol) and the reaction mixtureheated in a sealed vial at 80° C. for 5 hours. The reaction mixture wasmicrofiltered and purified by prep LCMS (10-99% ACN/Water, 5 mM HClmodifier) to give[10-(2-hydroxyethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(16 mg, 87%) as a colorless oil ESI-MS m/z calc. 458.2. found 459.7(M+1)⁺; Retention time: 1.78 minutes (3 min run).

Preparation of(4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone

Step 1:

T3P (546 mg, 510 μL of 50% w/w, 0.86 mmol) was added to a solution of8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylicacid (160 mg, 0.34 mmol), N′-hydroxyacetamidine (25 mg, 0.34 mmol) andtriethylamine (173 mg, 239 μL, 1.71 mmol) in 2-methyltetrahydrofuran(800 μL) and the reaction mixture was heated at 75° C. for 2 hours. Thereaction mixture was cooled to room temperature and partitioned betweenEtOAc/saturated aq. NaHCO₃. The layers were separated and the aqueouslayer was extracted with EtOAc (2×). The combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo to a dark foam. Thecrude product was purified by silica gel column chromatography using0-30% EtOAc in DCM as eluent to afford[8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(67 mg, 39%) as a white solid. ESI-MS m/z calc. 504.6. found 505.3(M+1)⁺; Retention time: 1.63 minutes (3 min run).

Step 2:

A solution of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) in DCE (0.1mL) was added to a stirred solution of[8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone(67 mg, 0.13 mmol) in DCE (488 μL) under an atmosphere of nitrogen andthe reaction mixture was heated to reflux. After 1 hour, an additionalaliquot of 1-chloroethyl chloroformate (89 μL, 0.80 mmol) was added andthe reaction mixture was heated to reflux for a further 8 hours. After 8hours, an additional 1-chloroethyl chloroformate (89 μL, 0.80 mmol) wasadded and the reaction mixture was heated to reflux for a further 15hours. The excess solvent was removed under reduced pressure and thecarbamate intermediate was dissolved in MeOH (2 mL) and heated at refluxfor 1 hour. The reaction mixture was cooled to room temperature,filtered and purified by Waters mass directed LC/MS-HPLC: (10-99%ACN/H2O (5 mM HCl)) to afford(4-isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanonehydrochloride salt (28 mg, 47%). ESI-MS m/z calc. 414.2. found 415.7(M+1)⁺; Retention time: 1.54 minutes (3 min run).

Step 3:

A mixture of(4-isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanonehydrochloride salt (28 mg, 0.06 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (14 μL, 0.09 mmol) and NaHCO₃ (21 mg, 0.23mmol) was heated at 80° C. in a sealed vial for 18 hours. The reactionmixture was allowed to cool to room temperature, microfiltered andpurified by Waters mass directed LC/MS: (10-99% ACN/H₂O (5 mM HCl)) andconcentrated to yield(4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(3 mg, 10%) as a white solid. ESI-MS m/z calc. 496.5. found 497.7(M+1)⁺; Retention time: 1.99 minutes (3 min run); ¹H NMR (400 MHz, DMSO)δ 7.27-7.06 (m, 2H), 6.96 (d, J=9.1 Hz, 1H), 5.17 (dd, J=13.6, 4.2 Hz,1H), 4.63 (dt, J=12.1, 6.2 Hz, 1H), 3.31-3.19 (m, 5H), 2.92-2.81 (m,1H), 2.67 (dd, J=12.0, 10.1 Hz, 1H), 2.43-2.27 (m, 6H), 2.15 (s, 3H),1.70-1.40 (m, 4H), 1.29 (d, J=6.0 Hz, 6H).

Preparation of8-ethyl-3-(4-isopropoxy-3-methyl-benzoyl)-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-9-one

Step 1:

To a mixture of tert-butyl4-hydroxy-4-[[(4-methoxyphenyl)methylamino]methyl]piperidine-1-carboxylate(1.06 g, 3.01 mmol) and diisopropylethylamine (1 mL, 5.74 mmol) in DCM(15 mL) at 0° C. was added 2-chloro-2-phenyl-acetyl chloride (654 mg,3.46 mmol) and the reaction mixture was stirred at room temperature for16 hours. The reaction mixture was concentrated in vacuo and the residuewas purified by silica gel column chromatography using 0-100% EtOAc/DCMas eluent to give tert-butyl4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate(1.11 g, 73%) as a pale yellow oil. ESI-MS m/z calc. 502.2. found 503.5(M+1)⁺; Retention time: 1.90 minutes (3 min run).

Step 2:

To a suspension of tert-butyl4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate(322 mg, 0.64 mmol) in DMF (3 mL) at 0° C. was added NaH (27 mg, 0.67mmol). The reaction mixture was allowed to warm to room temperatureovernight, then diluted with water (10 mL) and extracted with ethylacetate (3×15 mL). The combined organic layers were washed with water(10 mL) and brine (10 mL), dried over MgSO₄, filtered, and concentratedin vacuo. The crude product was purified by silica gel columnchromatography using 0-40% EtOAc/DCM to give tert-butyl10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate(215 mg, 72%) as a colorless oil. ESI-MS m/z calc. 502.2. found 503.5(M+1)⁺; Retention time: 1.90 minutes (3 min run).

Step 3:

To tert-butyl10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate(215 mg, 0.46 mmol) in acetonitrile (2.5 mL) was added water (2.5 mL)followed by the addition of ceric ammonium nitrate (500 mg, 0.91 mmol).The reaction mixture was stirred for 2 hours. After this time, a furtheraliquot of ceric ammonium nitrate (250 mg, 0.46 mmol) was added and thereaction mixture was stirred for an additional 45 minutes, it was thendiluted with 1M aq. HCl, extracted with ethyl acetate (2×25 mL), driedover MgSO₄ and concentrated in vacuo. The residue was dissolved inmethanol (1 mL) and HCl (1 mL of 4 M in dioxane, 4.00 mmol) was added.The reaction mixture was stirred for 1 hour, then concentrated in vacuoto give 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-9-one hydrochloridesalt (130 mg, 100%). ESI-MS m/z calc. 246.1. found 247.5 (M+1)⁺;Retention time: 0.46 minutes (3 min run).

Step 4:

To 4-isopropoxy-3-methyl-benzoic acid (114 mg, 0.59 mmol),4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one hydrochloride salt (166mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) in DMF (0.5 mL) was addeddiisopropylethylamine (228 mg, 307 μL, 1.76 mmol) and the reactionmixture was stirred for 16 hours. The reaction mixture was concentratedin vacuo, diluted with methanol and purified by prep LCMS (1-99%ACN/H₂O, 5 mM HCl modifier) to give3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one(100 mg, 40%) as a yellow foam. ESI-MS m/z calc. 422.2. found 423.5(M+1)⁺; Retention time: 1.61 minutes (3 min run).

Step 5:

To a solution of3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one(65 mg, 0.15 mmol) in THF (1 mL) at 0° C. was added NaH (6 mg, 0.15mmol) and the reaction mixture was stirred for 30 minutes. Bromoethane(34 mg, 23 μL, 0.31 mmol) was added and the reaction mixture was stirredat room temperature for 16 hours. The reaction mixture was concentratedin vacuo and purified by silica gel column chromatography using 0-100%EtOAc/DCM as eluent to give2-ethyl-9-(4-isopropoxy-3-methyl-benzoyl)-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-oneas a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.43 (m, 2H), 7.39-7.29(m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 4.56(dt, J=12.1, 6.0 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.59-3.19 (m, 5H),3.09 (d, J=12.4 Hz, 1H), 2.92 (d, J=28.7 Hz, 1H), 2.22 (s, 1H),2.23-2.16 (m, 3H), 1.59 (s, 3H), 1.35 (d, J=6.0 Hz, 6H), 1.14 (t, J=7.2Hz, 3H). ESI-MS m/z calc. 450.3. found 451.1 (M+1)⁺; Retention time:1.76 minutes (3 min run).

Preparation of2-isopentyl-9-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one

Step 1:

NaBH₄ (66 mg, 1.75 mmol) was added portionwise to a stirred solution of4-(aminomethyl)-1-benzyl-piperidin-4-ol (167 mg, 0.76 mmol) and3-methylbutanal (74 μL, 0.68 mmol) in MeOH (7.5 mL) and acetic acid (350μL). The reaction mixture was stirred for 16 hours at room temperature,then quenched with H₂O (5 mL). The aqueous layer was extracted withEtOAc (3×50 mL). The combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo to provide an oil. To the oil was addedpyridine (1 mL) followed by dropwise addition of (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (105 μL, 0.76 mmol) at room temperature. Thereaction mixture was stirred vigorously for 30 minutes. The reactionmixture was quenched with water and aqueous layer was extracted withEtOAc (3×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography using0-100% hexanes/EtOAc to provideN-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide(112 mg, 38%) as a pale tan oil.

Step 2:

Palladium (50.8 mg, 0.48 mmol) 10% on activated carbon andN-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide(112 mg, 0.29 mmol) in propan-2-ol (3 mL) was stirred under anatmosphere of hydrogen for 18 hours. The catalyst was filtered throughCelite® and washed with MeOH. The organics were concentrated in vacuo toprovide a clear oil. To the oil was added DMF (2 mL) and triethylamine(40 μL, 0.29 mmol) and this solution was added dropwise to a solution4-methoxy-3-(trifluoromethyl)benzoic acid (64 mg, 0.29 mmol) and HATU(110 mg, 0.29 mmol) in DMF (1 mL). The reaction mixture was stirred for16 hours. The solution was partitioned between water and EtOAc and thelayers were separated. The aqueous layer was extracted with EtOAc (3×100mL). The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was taken up in MeOH and purified byreverse phase HPLC (Gilson 20-99% water/MeOH) to give2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide(82 mg, 56%). ESI-MS m/z calc. 498.5. found 499.5 (M+1)⁺; Retentiontime: 1.86 minutes (3 min run).

Step 3:

Sodium hydroxide (1.4 mL of 0.2 M, 0.29 mmol) was added to a solution of2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide(72 mg, 0.14 mmol) in MeOH (722 μL) and the reaction mixture was heatedto 65° C. for 16 hours. The solution was partitioned between water (5mL) and EtOAc (5 mL) and the aqueous layer was extracted with EtOAc (3×5mL). The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide the crude amine as a clear oil (54 mg,92%). ESI-MS m/z calc. 402.4. found 403.7 (M+1)⁺; Retention time: 1.34minutes (3 min run). The residue was taken up in THF (480 μL) and addeddropwise to a solution of potassium tert-butoxide (36 mg, 0.32 mmol) intert-butanol (480 μL) and the reaction mixture was heated at 83° C. for20 minutes. The solution was neutralized with AcOH, and partitionedbetween water (2 mL) and EtOAc (2 mL), the aqueous layer was extractedwith EtOAc (3×2 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(3 mL) and purified by reverse phase HPLC (Gilson) 20-99% water/MeOH toprovide2-isopentyl-9-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one(39 mg, 45%) as a white foam. ESI-MS m/z calc. 518.6. found 519.5(M+1)⁺; Retention time: 2.03 minutes (3 min run).

Preparation of(3,3-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

Step 1:

2-(Benzylamino)-2-methyl-propan-1-ol hydrochloride (539 mg, 2.50 mmol)was treated with aqueous sodium hydroxide (50 mL of 2 M, 100 mmol), thendiethyl ether (50 mL) was added to the solution and stirred for 3 min.The organic layer was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to provide the2-(benzylamino)-2-methyl-propan-1-ol free base as a white powder. The2-(benzylamino)-2-methyl-propan-1-ol (2.50 mmol) and tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.344 mmol) weredissolved in ethanol (2 mL) and the reaction mixture was heated in asealed tube at 100° C. for 48 h. The ethanol was evaporated and thecrude material purified by silica gel column chromatography (1-100%ethyl acetate/hexanes) to provide tert-butyl4-((benzyl(1-hydroxy-2-methylpropan-2-yl)amino)methyl)-4-hydroxypiperidine-1-carboxylateas white powder (551 mg, 60%). ESI-MS m/z calc. 392.5. found 373.3(M+1)⁺; Retention time: 1.14 minutes (3 min run). ¹H NMR (400 MHz,DMSO-d₆) δ 7.43 (d, J=7.4 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.13 (t,J=7.3 Hz, 1H), 4.66 (t, J=5.1 Hz, 1H), 4.43 (s, 1H), 3.91 (s, 2H), 3.62(s, 2H), 3.22 (d, J=4.8 Hz, 2H), 2.97 (s, 2H), 2.58 (s, 2H), 1.44-1.27(m, 13H), 0.88 (s, 6H).

Step 2:

To a solution of tert-butyl4-[[benzyl-(2-hydroxy-1,1-dimethyl-ethyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate(330 mg, 0.841 mmol) in tetrahydrofuran was addedN,N-diisopropylethylamine (439 μL, 2.52 mmol) and methanesulfonicanhydride (439 mg, 2.52 mmol) under a nitrogen atmosphere. The reactionmixture was heated at 65° C. for 18 h. The reaction mixture was dilutedwith ethyl acetate, washed with saturated sodium bicarbonate (2×50 mL)and brine (50 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by silica gel chromatography(0-80% of ethyl acetate/hexanes) to provide tert-butyl8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(89 mg, 28%) as white solid. ESI-MS m/z calc. 374.5. found 375.3 (M+1)⁺;Retention time: 1.30 minutes (3 min run).

Step 3:

Tert-butyl8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate(89 mg, 0.24 mmol) was treated with hydrogen chloride solution indioxane (240 μL of 4 M, 0.95 mmol). The reaction mixture was stirred for18 h. The reaction mixture was concentrated in vacuo to provide8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride(56 mg, 86%). ESI-MS m/z calc. 274.4. found 275.5 (M+1)⁺; Retentiontime: 0.80 minutes (3 min run).

Step 4:

A solution of 4-isopropoxy-3-methylbenzoic acid (31.0 mg, 0.161 mmol)and O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (61.3 mg, 0.161 mmol) in acetonitrile was treatedwith triethylamine (67 μL, 0.48 mmol) and stirred for 5 min.8-Benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride(56.0 mg, 0.161 mmol) was added and the reaction mixture stirred for 3h. The reaction mixture was filtered and concentrated in vacuo. Thecrude material was purified by chromatography (0-80% of ethylacetate/hexanes) to provide(8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(51.0 mg, 70%) as colorless oil. ESI-MS m/z calc. 450.6. found 451.3(M+1)⁺; Retention time: 1.54 minutes (3 min run).

Step 5:

To a solution of(8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(51 mg, 0.11 mmol) in ethanol (2 mL) was added Pd(OH)₂ (16 mg, 0.11mmol) followed by ammonium formate (29 mg, 0.45 mmol). The reactionmixture was stirred at 40° C. for 18 h, then filtered and concentratedin vacuo to afford(9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(40 mg, 98%). ESI-MS m/z calc. 360.5. found 361.3 (M+1)⁺; Retentiontime: 1.29 minutes (3 min run).

Preparation of(8-but-2-ynyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone

To a mixture of(9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(20.1 mg, 0.0557 mmol) and potassium carbonate (15 mg, 0.11 mmol) inN,N-dimethylformamide (310 μL) was added 1-bromobut-2-yne (8.1 mg, 0.061mmol) and reaction mixture was heated at 45° C. for 1 h. The reactionmixture was filtered and crude material was purified by HPLC (15-75%CH₃CN/5 mM HCl) to provide(8-but-2-ynyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanonehydrochloride (11 mg, 41%). ESI-MS m/z calc. 412.3. found 413.3 (M+1)⁺;Retention time: 1.43 minutes (3 min run).

Preparation of(3,3-dimethyl-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

A solution of(9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone(11.0 mg, 0.0305 mmol), potassium carbonate (4.2 mg, 0.031 mmol) and2-chloropyrimidine (3.7 mg, 0.031 mmol) in DMSO (90 μL) was heated at90° C. for 2 h. The reaction was filtered and purified by HPLC (1-99%CH₃CN/5 mM HCl) to provide(3,3-dimethyl-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanonehydrochloride (6.0 mg, 0.012 mmol, 38%). ESI-MS m/z calc. 438.3. found439.3 (M+1)⁺; Retention time: 1.92 minutes (3 min run).

Preparation of(4-isopropoxy-3-methylphenyl)(2-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methanone

To a vial charged with(4-isopropoxy-3-methyl-phenyl)-[10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(30.0 mg, 0.08 mmol), 1-bromo-4-(trifluoromethyl)benzene (19.7 mg, 0.088mmol), Pd₂(dba)₃ (23 mg, 0.04 mmol), rac-BINAP (24.8 mg, 0.04 mmol) andsodium tert-butoxide (9.8 mg, 0.088 mmol) were addedN-methyl-2-pyrrolidone (0.2 mL) and toluene (1.0 mL). The reactionmixture was heated at 100° C. under nitrogen 18 h. The reaction mixturewas cooled to room temperature, filtered and purified via HPLC (1-90%CH₃CN/5 mM HCl) to provide(4-isopropoxy-3-methylphenyl)(2-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methanone(5.0 mg, 0.0077 mmol, 10%). ESI-MS m/z calc. 520.2549. found 521.3(M+1)⁺; Retention time: 2.21 minutes (3 min run).

Preparation of(4-cyclobutyl-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone

Step 1:

A solution of(4-isopropoxy-3-methyl-phenyl)-[10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone(343 mg, 0.912 mmol) and cyclobutanone (96.0 mg, 1.36 mmol) indichloroethane (3 mL) was treated with acetic acid (78 μL, 1.4 mmol) andstirred for 30 min. NaBH(OAc)₃ (387 mg, 1.82 mmol) was added and thereaction mixture stirred for 16 h. The reaction mixture was diluted withMTBE and washed with 1N NaOH (100 mL). The organic layer was separatedand washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (5-80% ethyl acetate/hexane) provided(4-cyclobutyl-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone(330 mg, 84%). ESI-MS m/z calc. 430.3. found 431.3 (M+1)⁺; Retentiontime: 1.24 minutes (3 min run). ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8.4Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 4.55 (hept, J=6.2 Hz, 1H), 4.30-4.10(m, 1H), 3.94-3.75 (m, 1H), 3.62-3.46 (m, 1H), 3.48-3.33 (m, 6H),3.30-3.16 (m, 1H), 2.75 (d, J=10.8 Hz, 1H), 2.67-2.57 (m, 1H), 2.55 (d,J=11.1 Hz, 1H), 2.47-2.27 (m, 1H), 2.20 (s, 3H), 1.98 (d, J=7.3 Hz, 2H),1.91-1.76 (m, 1H), 1.76-1.61 (m, 4H), 1.57-1.39 (m, 3H), 1.34 (d, J=6.0Hz, 6H).

Table 2 below recites the analytical data for the compounds of Table 1.

TABLE 2 Cmpd. LC/MS LC/RT No. M + 1 min NMR 1 467.50 1.63 2 467.30 1.013 490.20 1.22 4 507.14 1.87 5 473.39 1.42 6 411.50 1.90 7 423.50 1.31 8497.23 2.41 9 451.10 1.76 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 2H),7.39-7.29 (m, 3H), 7.23-7.17 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 5.11 (s,1H), 4.56 (dt, J = 12.1, 6.0 Hz, 1H), 3.63 (d, J = 12.4 Hz, 1H),3.59-3.19 (m, 5H), 3.09 (d, J = 12.4 Hz, 1H), 2.92 (d, J = 28.7 Hz, 1H),2.22 (s, 1H), 2.23-2.16 (m, 3H), 1.59 (s, 4H), 1.35 (d, J = 6.0 Hz, 6H),1.14 (t, J = 7.2 Hz, 3H). 10 437.70 1.43 11 477.40 6.04 1H NMR (400 MHz,CD3CN) δ 7.39 (d, J = 1.9 Hz, 1H), 7.26-7.10 (m, 2H), 6.92 (d, J = 9.0Hz, 1H), 6.54 (t, J = 52.5 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.28 (d, J= 9.5 Hz, 1H), 4.63 (dt, J = 12.1, 6.0 Hz, 1H), 3.90 (s, 4H), 3.42 (d, J= 12.1 Hz, 1H), 3.24 (d, J = 12.4 Hz, 6H), 2.92 (d, J = 27.2 Hz, 3H),2.74 (s, 2H), 2.51-2.01 (m, 33H), 1.87-1.46 (m, 5H), 1.30 (t, J = 10.1Hz, 7H). 12 539.29 1.97 13 492.30 2.26 14 468.19 2.37 15 471.29 2.33 16468.30 1.51 17 468.50 1.25 18 417.30 1.43 19 459.29 2.78 20 491.50 1.821H NMR (400 MHz, CD3CN) δ 7.45 (d, J = 1.7 Hz, 1H), 7.23-7.16 (m, 2H),7.13 (t, J = 3.8 Hz, 1H), 6.98-6.88 (m, 1H), 6.63 (s, 1H), 6.50 (s, 1H),6.34 (s, 1H), 6.29 (d, J = 1.7 Hz, 1H), 5.29 (d, J = 8.6 Hz, 1H),4.74-4.54 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.50-3.09 (m, 6H),3.05-2.59 (m, 3H), 2.46-2.03 (m, 6H), 1.89-1.75 (m, 2H), 1.75-1.50 (m,2H), 1.49-1.39 (m, 3H), 1.34 (dd, J = 6.0, 5.1 Hz, 6H), 1.29 (s, 1H),1.17 (d, J = 6.1 Hz, 2H). 21 463.30 1.71 1H NMR (400 MHz, MeOD) δ 7.70(d, J = 2.3 Hz, 1H), 7.30-7.16 (m, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.43(d, J = 2.3 Hz, 1H), 6.27 (s, 1H), 6.14 (s, 1H), 6.00 (s, 1H), 5.01 (d,J = 43.6 Hz, 1H), 4.66 (dt, J = 12.0, 6.0 Hz, 1H), 4.30 (s, 1H), 3.49(ddd, J = 49.9, 49.0, 23.7 Hz, 3H), 3.19-2.96 (m, 3H), 2.60 (dd, J =42.6, 23.4 Hz, 3H), 2.19 (s, 3H), 1.68 (s, 3H), 1.34 (d, J = 6.0 Hz,6H). 22 437.70 1.36 23 416.29 1.62 24 481.70 1.49 25 453.20 1.08 26495.50 7.63 27 491.25 2.17 28 389.70 1.03 29 465.70 1.72 30 439.10 1.3831 454.30 1.29 32 391.30 1.20 33 474.50 1.61 34 389.70 1.36 35 477.301.50 1H NMR (400 MHz, DMSO) δ 7.74 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.9Hz, 1H), 7.18 (dd, J = 6.0, 2.0 Hz, 2H), 7.04-6.90 (m, 1H), 6.20 (tt, J= 55.5, 4.0 Hz, 1H), 5.34-5.28 (m, 1H), 4.69-4.57 (m, 1H), 3.91 (s, 3H),3.69-3.41 (m, 1H), 3.37-3.09 (m, 3H), 2.87 (ddd, J = 19.6, 18.4, 7.9 Hz,3H), 2.57-2.51 (m, 2H), 2.46-2.31 (m, 1H), 2.26 (d, J = 11.6 Hz, 1H),2.13 (s, 3H), 1.70-1.52 (m, 3H), 1.29 (d, J = 6.0 Hz, 6H). 36 499.301.76 37 488.40 1.50 38 485.50 7.23 39 509.50 1.97 40 389.70 1.33 41442.50 1.12 42 492.20 2.17 43 453.50 1.24 44 491.30 2.27 1H NMR (400MHz, CDCl3) δ 7.53 (t, J = 6.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.20-7.09 (m,3H), 7.07-7.01 (m, 1H), 6.96 (t, J = 8.2 Hz, 1H), 6.14-5.75 (m, 1H),5.25-5.07 (m, 1H), 4.66-4.52 (m, 1H), 4.45-4.21 (m, 1H), 3.73-3.31 (m,2H), 3.08 (d, J = 10.8 Hz, 1H), 2.85-2.61 (m, 4H), 2.39-2.17 (m, 2H),1.66-1.45 (m, 3H), 1.37 (d, J = 6.1 Hz, 6H). 45 495.50 2.14 1H NMR (400MHz, CDCl3) δ 7.53 (t, J = 6.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.20-7.09 (m,3H), 7.07-7.01 (m, 1H), 6.96 (t, J = 8.2 Hz, 1H), 6.14-5.75 (m, 1H),5.25-5.07 (m, 1H), 4.66-4.52 (m, 1H), 4.45-4.21 (m, 1H), 3.73-3.31 (m,2H), 3.08 (d, J = 10.8 Hz, 1H), 2.85-2.61 (m, 4H), 2.39-2.17 (m, 2H),1.66-1.45 (m, 3H), 1.37 (d, J = 6.1 Hz, 6H). 46 415.50 1.41 47 445.371.33 48 447.33 1.34 49 470.30 1.38 50 465.50 1.64 51 439.30 1.92 52433.11 1.47 53 459.29 2.18 54 464.50 1.29 55 449.34 1.32 56 505.40 2.1657 478.20 1.06 58 525.29 1.81 59 489.28 1.85 60 521.50 2.15 61 535.203.25 62 525.00 2.00 63 487.30 2.39 64 458.18 2.22 65 522.40 1.13 66503.15 2.65 67 465.50 1.60 1H NMR (400 MHz, DMSO) δ 8.35 (d, J = 4.4 Hz,2H), 7.52 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 6.62 (s, 1H),4.75 (s, 1H), 4.65-4.48 (m, 2H), 4.10 (br s, 1H), 3.56 (br s, 1H), 3.39(br s, 1H), 3.03 (br s, 1H), 2.75 (d, J = 13.3 Hz, 1H), 2.60-2.52 (m,1H), 1.99 (br s, 1H), 1.81-1.17 (m, 16H), 0.96 (t, J = 7.3 Hz, 3H). 68448.24 1.64 69 469.20 2.17 70 478.30 1.94 71 467.10 2.10 72 427.29 2.5273 419.31 1.28 74 483.30 2.03 75 468.30 1.14 76 474.50 1.07 77 477.302.15 78 518.38 2.05 79 484.30 1.59 80 492.50 1.16 81 507.00 1.86 1H NMR(400 MHz, MeOD) δ 7.47 (dd, J = 8.7, 5.4 Hz, 2H), 7.23 (dd, J = 11.7,3.5 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.24(t, J = 54.0 Hz, 1H), 4.95 (s, 1H), 4.33 (s, 1H), 4.13 (t, J = 6.2 Hz,2H), 3.77 (t, J = 6.3 Hz, 2H), 3.73-3.61 (m, 1H), 2.73 (s, 2H),2.61-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.96 (m, 2H), 1.75 (s, 3H). 82453.50 1.19 83 504.50 1.70 84 481.50 1.62 85 534.40 1.15 86 493.40 2.1387 499.30 7.16 1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J = 15.8, 5.3 Hz,2H), 7.06-6.86 (m, 1H), 6.17 (s, 1H), 5.01 (s, 1H), 4.58 (dt, J = 12.2,6.1 Hz, 1H), 4.30 (s, 1H), 3.60 (s, 3H), 3.15 (d, J = 11.6 Hz, 1H), 3.01(q, J = 9.3 Hz, 2H), 2.74 (d, J = 11.1 Hz, 1H), 2.59 (dd, J = 20.7, 9.9Hz, 2H), 2.47 (d, J = 11.4 Hz, 1H), 2.44 (s, 3H), 2.02 (d, J = 6.7 Hz,1H), 1.78 (d, J = 45.0 Hz, 1H), 1.53 (d, J = 6.1 Hz, 2H), 1.44-1.23 (m,6H). 88 506.30 2.09 89 443.36 1.42 90 485.12 2.07 91 451.30 1.55 92441.30 1.55 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 7.20 (d, J = 9.0 Hz,2H), 6.80 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.80 (dd, J = 22.7, 12.7Hz, 2H), 4.55 (dt, J = 12.0, 6.0 Hz, 1H), 3.92 (dt, J = 7.4, 6.6 Hz,1H), 3.83-3.64 (m, 3H), 3.59-3.42 (m, 1H), 3.28 (s, 1H), 3.08-2.88 (m,2H), 2.19 (s, 3H), 2.11-1.87 (m, 2H), 1.80-1.52 (m, 3H), 1.34 (d, J =6.0 Hz, 6H). 93 467.50 1.29 94 495.40 2.27 95 468.32 2.40 96 553.12 1.7597 438.50 1.11 98 491.30 2.12 99 538.28 1.91 100 489.70 2.17 1H NMR (400MHz, CDCl3) δ 7.45-7.36 (m, 5H), 6.98-6.83 (m, 3H), 5.25 (d, J = 10.4Hz, 1H), 4.57 (dt, J = 12.2, 6.1 Hz, 1H), 3.85 (s, 3H), 3.60 (d, J =10.9 Hz, 1H), 3.47-3.12 (m, 6H), 2.86-2.60 (m, 3H), 1.88-1.50 (m, 5H),1.38 (d, J = 6.1 Hz, 6H). 101 433.35 1.34 102 485.16 2.65 103 464.501.25 104 507.50 2.26 105 477.30 2.05 106 459.20 1.91 107 463.38 1.40 108511.26 1.85 109 539.15 1.95 110 501.30 7.66 111 433.35 1.29 112 461.361.42 113 433.29 1.19 114 483.50 1.89 115 464.24 1.59 116 474.30 2.08 117507.00 1.94 118 487.05 2.28 119 477.32 2.14 120 455.30 1.86 1H NMR (400MHz, CDCl3) δ 8.45 (d, J = 4.5 Hz, 2H), 7.23-7.17 (m, 2H), 6.80 (d, J =8.1 Hz, 1H), 6.71 (s, 1H), 4.97-4.76 (m, 2H), 4.55 (dt, J = 12.1, 6.0Hz, 1H), 4.36-4.08 (m, 1H), 4.03-3.84 (m, 1H), 3.81-3.61 (m, 1H),3.61-3.50 (m, 3H), 3.42 (s, 3H), 3.35-3.21 (m, 1H), 3.07-2.91 (m, 2H),2.19 (s, 3H), 2.07-1.93 (m, 1H), 1.84-1.52 (m, 3H), 1.34 (d, J = 6.0 Hz,6H). 121 502.35 1.17 122 507.20 2.17 123 505.30 2.50 1H NMR (501 MHz,DMSO) δ 7.38-7.26 (m, 5H), 7.15 (s, 2H), 6.92 (d, J = 8.5 Hz, 1H), 4.59(dt, J = 11.1, 5.4 Hz, 1H), 4.29 (s, 1H), 3.52-3.44 (m, 2H), 3.24-2.98(m, 3H), 2.91 (d, J = 11.6 Hz, 1H), 2.71-2.47 (m, 3H), 2.46-2.27 (m,1H), 2.10 (s, 3H), 1.67-1.38 (m, 3H), 1.26 (d, J = 5.8 Hz, 6H), 0.79 (d,J = 5.1 Hz, 3H). 124 521.30 2.22 125 487.29 2.14 126 484.30 1.40 127473.50 1.94 128 521.34 2.16 129 427.50 1.61 130 451.50 2.03 131 477.291.30 132 472.18 2.48 133 491.30 2.09 1H NMR (400 MHz, CDCl3) δ 7.43-7.30(m, 8H), 7.26 (s, 1H), 4.86 (s, 1H), 4.47-4.27 (m, 1H), 3.66-3.12 (m,3H), 3.04 (dd, J = 18.6, 9.3 Hz, 3H), 2.84 (s, 2H), 2.81 (s, 2H),2.73-2.54 (m, 1H), 2.52-2.37 (m, 2H), 1.86-1.74 (m, 2H), 1.26 (s, 6H).134 475.34 1.23 135 495.13 2.22 136 441.29 2.70 137 524.10 2.22 138521.30 2.04 139 417.30 1.37 140 454.30 0.28 141 385.30 1.22 142 451.501.35 143 523.29 1.89 144 432.18 1.87 145 439.70 1.26 146 459.70 1.78 147447.33 1.42 148 505.30 1.63 149 497.70 1.99 1H NMR (400 MHz, DMSO) δ7.27-7.06 (m, 2H), 6.96 (d, J = 9.1 Hz, 1H), 5.17 (dd, J = 13.6, 4.2 Hz,1H), 4.63 (dt, J = 12.1, 6.2 Hz, 1H), 3.31-3.19 (m, 5H), 2.92-2.81 (m,1H), 2.67 (dd, J = 12.0, 10.1 Hz, 1H), 2.43-2.27 (m, 6H), 2.15 (s, 3H),1.70-1.40 (m, 4H), 1.29 (d, J = 6.0 Hz, 6H). 150 477.30 1.59 151 491.141.72 152 528.50 1.92 153 473.26 2.23 154 421.30 2.00 1H NMR (400 MHz,CDCl3) δ 7.25-7.16 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 4.56 (dt, J =12.1, 6.0 Hz, 1H), 3.85-3.57 (m, 2H), 3.41 (br s, 2H), 3.36 (d, J = 2.3Hz, 2H), 2.88-2.76 (m, 2H), 2.51 (s, 2H), 2.20 (s, 3H), 2.09 (d, J =14.2 Hz, 2H), 1.85 (t, J = 2.3 Hz, 3H), 1.54 (br s, 2H), 1.34 (d, J =6.0 Hz, 6H). 155 453.10 2.13 156 511.16 2.14 157 441.20 1.82 158 423.700.93 159 510.30 1.98 160 433.50 1.25 161 441.29 2.00 162 522.60 1.43 163409.50 1.32 1H NMR (400 MHz, MeOD) δ 7.49-7.32 (m, 5H), 7.24-7.16 (m,2H), 6.98-6.90 (m, 1H), 5.08-4.96 (m, 1H), 4.70-4.60 (m, 1H), 4.48-4.28(m, 1H), 3.86-3.62 (m, 1H), 3.60-3.32 (m, 3H), 3.21-2.91 (m, 3H),2.69-2.43 (m, 1H), 2.19 (s, 3H), 1.96-1.55 (m, 3H), 1.34 (d, J = 6.0 Hz,6H). 164 449.24 2.42 165 539.29 2.02 166 453.50 1.08 167 484.70 0.99 168473.26 1.83 169 467.30 1.2 1H NMR (400 MHz, DMSO) δ 7.36-7.27 (m, 4H),7.24 (t, J = 6.7 Hz, 1H), 7.20-7.12 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H),4.63 (dt, J = 12.1, 6.0 Hz, 1H), 3.95-3.78 (m, 1H), 3.44 (dd, J = 30.4,13.6 Hz, 3H), 3.34 (d, J = 5.5 Hz, 2H), 3.29-3.19 (m, 5H), 3.18-3.01 (m,1H), 2.73 (d, J = 10.3 Hz, 1H), 2.69-2.56 (m, 1H), 2.33 (d, J = 1.9 Hz,1H), 2.12 (s, 3H), 1.75 (t, J = 11.0 Hz, 2H), 1.53-1.34 (m, 3H), 1.28(d, J = 6.0 Hz, 6H). 170 521.00 1.93 1H NMR (400 MHz, MeOD) δ 7.48 (dd,J = 8.7, 5.4 Hz, 2H), 7.32-7.19 (m, 2H), 7.13 (dd, J = 12.2, 5.4 Hz,2H), 6.93 (d, J = 8.1 Hz, 1H), 6.22 (d, J = 55.6 Hz, 1H), 4.95 (s, 1H),4.36 (s, 1H), 3.82 (s, 2H), 3.75-3.64 (m, 1H), 3.57-3.36 (m, 4H), 2.84(d, J = 9.5 Hz, 2H), 2.65 (s, 1H), 2.27 (s, 3H), 1.76 (s, 3H), 1.35 (s,6H). 171 491.50 1.86 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 4.8 Hz, 2H),7.24-7.15 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.53 (t, J = 4.7 Hz, 1H),6.29 (t, J = 74.3 Hz, 1H), 4.75 (d, J = 13.0 Hz, 1H), 4.65 (d, J = 13.3Hz, 1H), 4.55 (dt, J = 12.1, 6.1 Hz, 1H), 3.93 (m, 3H), 3.52 (br s, 2H),3.37-3.17 (m, 1H), 2.88-2.73 (m, 2H), 2.19 (s, 3H), 2.03 (br s, 1H),1.71-1.53 (m, 3H), 1.34 (d, J = 6.1 Hz, 6H). 172 527.26 1.82 173 471.292.50 174 484.30 1.39 175 449.34 1.28 176 450.50 1.17 177 478.10 2.21 1HNMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 8.7 Hz,1H), 7.43-7.30 (m, 5H), 7.28-7.25 (m, 1H), 4.85 (dd, J = 33.8, 8.9 Hz,1H), 4.64 (dq, J = 12.0, 6.0 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H),3.88-3.77 (m, 1H), 3.70-3.14 (m, 2H), 3.07-2.91 (m, 3H), 2.82-2.55 (m,2H), 2.40 (dd, J = 22.0, 10.9 Hz, 2H), 1.76-1.60 (m, 3H), 1.40 (d, J =6.0 Hz, 6H). 178 441.30 1.48 179 481.70 1.24 180 460.30 1.40 181 495.701.95 182 463.57 1.82 183 483.30 1.95 184 451.29 1.32 185 413.36 1.43 186519.50 2.03 187 473.30 1.91 188 435.30 1.24 189 511.26 1.87 190 511.502.25 1H NMR (400 MHz, DMSO) δ 7.61 (dd, J = 7.8, 1.2 Hz, 1H), 7.50-7.31(m, 3H), 7.30-7.12 (m, 3H), 6.36-6.00 (m, 1H), 5.08 (d, J = 13.4 Hz,1H), 4.74-4.64 (m, 1H), 4.12-3.91 (m, 1H), 3.73-3.59 (m, 2H), 3.32 (dd,J = 32.0, 10.6 Hz, 1H), 3.06 (dd, J = 11.0, 3.1 Hz, 1H), 2.91 (dd, J =11.6, 2.6 Hz, 1H), 2.86-2.65 (m, 2H), 2.44-2.30 (m, 1H), 2.19 (d, J =9.6 Hz, 1H), 2.13-1.99 (m, 1H), 1.70-1.55 (m, 3H), 1.30 (d, J = 6.0 Hz,6H). 191 469.33 3.47 192 453.50 1.10 193 475.30 1.38 194 507.29 1.94 195492.20 1.31 196 512.70 2.17 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.20(d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.1 Hz, 1H), 5.20 (dd, J = 9.3, 1.1Hz, 1H), 4.62-4.52 (m, 1H), 3.76 (ddd, J = 36.3, 29.5, 14.8 Hz, 1H),3.50 (dd, J = 10.4, 1.0 Hz, 2H), 3.33-3.13 (m, 1H), 3.05 (q, J = 9.3 Hz,2H), 2.77 (d, J = 11.3 Hz, 1H), 2.60-2.42 (m, 6H), 2.20 (s, 3H),1.79-1.46 (m, 4H), 1.35 (d, J = 6.0 Hz, 6H). 197 455.29 2.34 198 502.272.21 199 493.00 1.87 200 539.00 2.06 201 473.39 1.40 202 511.16 1.80 203439.70 1.21 204 459.30 1.44 205 419.31 1.26 206 473.39 1.44 207 481.501.43 208 487.22 2.12 209 464.30 1.77 1H NMR (400 MHz, CDCl3) δ 7.74 (d,J = 0.7 Hz, 1H), 7.22-7.17 (m, 2H), 7.16 (d, J = 0.7 Hz, 1H), 7.04-6.70(m, 2H), 5.44 (dd, J = 10.9, 1.9 Hz, 1H), 4.64-4.52 (m, 1H), 4.41-4.22(m, 1H), 4.17-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.47-3.27 (m, 6H), 3.23(d, J = 15.1 Hz, 1H), 2.81 (d, J = 12.3 Hz, 1H), 2.20 (s, 3H), 1.82-1.62(m, 3H), 1.36 (d, J = 6.0 Hz, 6H). 210 479.20 1.10 211 481.30 7.73 1HNMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 8.6 Hz,2H), 6.80 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 5.06 (s, 1H), 4.55 (dt, J =12.1, 6.1 Hz, 1H), 3.41 (d, J = 73.7 Hz, 4H), 3.15 (d, J = 10.6 Hz, 1H),3.01 (q, J = 9.3 Hz, 2H), 2.77 (d, J = 11.4 Hz, 1H), 2.59 (dd, J = 19.2,8.3 Hz, 2H), 2.47 (d, J = 11.3 Hz, 1H), 2.15 (d, J = 37.6 Hz, 3H), 2.01(s, 1H), 1.64 (d, J = 48.9 Hz, 3H), 1.34 (d, J = 6.0 Hz, 6H). 212 449.201.83 213 511.70 2.48 214 492.30 2.00 215 449.34 1.27 216 485.50 1.32 217413.50 1.50 218 429.33 1.08 219 489.22 2.00 220 495.30 1.36 221 478.501.47 222 494.20 1.49 223 519.30 1.78 224 489.23 1.83 225 551.50 1.87 226467.30 1.57 227 441.70 1.23 228 478.31 1.83 229 491.30 1.89 1H NMR (400MHz, CD3CN) δ 7.54 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.2, 1.2 Hz, 2H),6.98 (t, J = 4.1 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.78 (dt, J = 53.9,4.1 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 5.26 (d, J = 10.2 Hz, 1H), 4.63(dt, J = 12.1, 6.0 Hz, 1H), 4.14 (q, J = 7.3 Hz, 2H), 3.63-3.35 (m, 5H),3.37-3.13 (m, 3H), 3.08 (d, J = 13.2 Hz, 1H), 2.95 (d, J = 12.6 Hz, 1H),2.64-2.02 (m, 11H), 1.73 (ddd, J = 26.1, 9.6, 3.2 Hz, 2H), 1.58 (d, J =14.5 Hz, 1H), 1.48-1.36 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). 230 520.302.34 231 424.15 1.35 232 473.33 1.42 233 443.70 2.33 234 525.00 2.28 235469.50 1.77 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.5 Hz, 2H), 7.20 (d,J = 8.8 Hz, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 4.85 (d, J =12.9 Hz, 1H), 4.76 (d, J = 13.1 Hz, 1H), 4.55 (dt, J = 12.1, 6.1 Hz,1H), 4.16 (s, 1H), 3.94 (s, 1H), 3.64-3.44 (m, 5H), 3.28 (t, J = 11.5Hz, 1H), 3.28 (t, J = 11.5 Hz, 1H), 2.92 (dd, J = 26.7, 12.5 Hz, 2H),2.19 (s, 3H), 2.03 (s, 2H), 1.65 (d, J = 47.5 Hz, 4H), 1.34 (d, J = 6.1Hz, 5H), 1.22 (t, J = 7.0 Hz, 3H). 236 439.50 1.87 1H NMR (400 MHz,CDCl3) δ 8.44 (d, J = 4.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.80 (d, J= 8.1 Hz, 1H), 6.69 (s, 1H), 4.86 (d, J = 13.3 Hz, 1H), 4.77 (d, J =12.4 Hz, 1H), 4.55 (dt, J = 12.3, 6.1 Hz, 1H), 3.66 (br s, 1H), 3.47 (brs, 1H), 3.17 (br s, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.81 (t, J = 12.2Hz, 1H), 2.20 (s, 3H), 2.03 (br s, 1H), 1.78-1.52 (m, 6H), 1.34 (d, J =6.1 Hz, 6H), 1.05 (t, J = 7.5 Hz, 3H). 237 481.50 1.43 238 487.50 1.48239 417.15 1.38 240 455.29 2.13 241 459.23 1.75 242 399.30 1.37 243468.50 1.61 244 495.20 2.07 245 505.28 1.98 246 474.24 2.03 247 521.202.12 248 413.30 1.47 249 459.35 1.26 250 458.70 1.28 251 489.50 2.00 252474.28 1.38 253 504.40 1.29 254 405.28 1.24 255 433.29 1.28 256 484.301.94 257 495.50 2.12 258 521.30 2.26 259 459.30 1.17 260 459.30 1.94 261492.20 1.32 262 459.50 1.51 263 481.10 1.66 264 453.50 1.23 265 536.701.23 266 465.50 1.93 267 455.29 2.20 268 474.30 1.33 269 539.15 1.90 270461.30 1.21 271 469.50 1.54 272 419.70 1.20 273 507.30 1.96 274 507.201.93 275 434.20 1.55 276 499.33 3.20 277 414.18 1.20 278 507.40 2.15 279508.40 1.44 280 538.17 1.83 281 451.50 1.38 282 456.31 2.33 283 448.202.01 284 481.24 2.79 285 431.34 1.25 286 453.30 1.98 287 431.33 1.03 288450.50 1.17 289 479.40 1.98 290 470.15 1.98 291 454.20 1.32 292 549.502.28 293 536.40 1.95 294 455.37 1.57 295 438.70 1.39 1H NMR (400 MHz,CDCl3) δ 8.21 (d, J = 5.7 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.25-7.19(m, 2H), 6.92 (d, J = 9.2 Hz, 1H), 6.88 (t, J = 6.6 Hz, 1H), 6.80 (d, J= 8.2 Hz, 1H), 4.55 (dt, J = 12.1, 6.1 Hz, 1H), 4.48 (d, J = 13.6 Hz,1H), 4.35 (d, J = 12.5 Hz, 1H), 3.77 (br s, 1H), 3.43 (br s, 1H), 3.20(d, J = 13.4 Hz, 1H), 3.12 (br s, 1H), 3.04-2.91 (m, 1H), 2.20 (s, 3H),2.09 (br s, 1H), 1.72-1.59 (m, 6H), 1.34 (d, J = 5.9 Hz, 6H), 1.07 (t, J= 7.4 Hz, 3H). 296 476.20 0.96 297 508.70 1.51 298 481.30 1.48 1H NMR(400 MHz, DMSO) δ 7.48 (s, 1H), 7.35-7.13 (m, 3H), 6.60-6.25 (m, 1H),5.06-4.91 (m, 1H), 4.75-4.64 (m, 1H), 4.27-3.99 (m, 1H), 3.58-2.55 (m,9H), 2.07 (s, 3H), 1.67-1.39 (m, 4H), 1.30 (d, J = 6.0 Hz, 6H). 299503.26 2.07 300 467.50 1.29 301 491.50 2.33 302 445.31 1.30 303 466.292.67 304 501.41 1.58 305 490.20 1.11 306 477.30 1.77 1H NMR (400 MHz,CD3CN) δ 7.50 (d, J = 2.3 Hz, 1H), 7.24-7.14 (m, 2H), 6.98 (s, 1H), 6.92(d, J = 9.1 Hz, 1H), 6.81 (dd, J = 31.0, 26.9 Hz, 1H), 6.35 (d, J = 2.3Hz, 1H), 5.26 (d, J = 9.6 Hz, 1H), 4.63 (dt, J = 12.0, 6.0 Hz, 1H), 3.85(s, 4H), 3.67-3.37 (m, 5H), 3.36-3.14 (m, 3H), 3.08 (d, J = 13.9 Hz,1H), 2.95 (d, J = 12.7 Hz, 1H), 2.70-2.03 (m, 14H), 1.97 (s, 1H),1.81-1.51 (m, 4H), 1.32 (t, J = 5.4 Hz, 7H). 307 495.10 1.88 308 424.501.14 309 496.70 1.99 1H NMR (400 MHz, DMSO) δ 7.27-7.13 (m, 2H), 6.96(d, J = 9.0 Hz, 1H), 6.82 (d, J = 1.2 Hz, 1H), 4.86 (dd, J = 12.0, 4.7Hz, 1H), 4.71-4.54 (m, 1H), 3.32-3.14 (m, 5H), 3.07 (dd, J = 11.5, 2.6Hz, 1H), 2.90-2.83 (m, 1H), 2.70 (dd, J = 18.3, 7.2 Hz, 1H), 2.41-2.23(m, 6H), 2.13 (s, 3H), 1.64-1.39 (m, 3H), 1.29 (d, J = 6.0 Hz, 6H).Assays for Detecting and Measuring NaV Inhibition Properties of CompoundE-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing human NaVsubtype, like NaV 1.7, are seeded in 384-well poly-lysine coated platesat 15,000-20,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest. HEK cellsare grown in media (exact composition is specific to each cell type andNaV subtype) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

Reagents and Solutions

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: 384-well round bottom plate, e.g. Corning 384-wellPolypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plate, e.g. Greiner#781091-1B

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Bath1 buffer. Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (make this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 μM DiSBAC₆(3). To make thesolution Add volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation is first mix Pluronic andCC2-DMPE, then add DiSBAC₆(3) while vortexing, then addBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spot compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds are added to each well at 160×desired final concentration in neat DMSO. Final compound plate volumewill be 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay is 0.625%.

2) Prepare Hexyl Dye Solution.

3) Prepare cell plates. On the day of the assay, medium is aspirated andcells are washed three times with 100 μL of Bath1 Solution, maintaining25 μL residual volume in each well.

4) Dispense 25 μL per well of Hexyl Dye Solution into cell plates.Incubate for 20-35 minutes at room temp or ambient conditions.

5) Dispense 80 μL per well of Bath1 into compound plates. Acid Yellow-17(1 mM) is added and Potassium Chloride can be altered from 4.5 to 20 mMdepending on the NaV subtype and assay sensitivity.

6) Wash cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transfer 25 uL per well from CompoundPlates to Cell Plates. Incubate for 20-35 minutes at room temp/ambientcondition

7) Read Plate on E-VIPR. Use the current-controlled amplifier to deliverstimulation wave pulses for typically 9 seconds and a scan rate of 400Hz. A pre-stimulus recording is performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform is appliedfor 9 seconds followed by 0.5 seconds of post-stimulation recording toexamine the relaxation to the resting state. The stimulatory waveform ofthe electrical stimulation is specific for each cell type and can varythe magnitude, duration and frequency of the applied current to providean optimal assay signal.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu}{nm}} - {background}_{460\mspace{11mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{11mu}{nm}} - {background}_{580\mspace{11mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated and reported as a function of time.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

IonWorks Assays.

Sodium currents were recorded using the automated patch clamp system,IonWorks (Molecular Devices Corporation, Inc.). Cells expressing Navsubtypes are harvested from tissue culture and placed in suspension at0.5-4 million cells per mL Bath1. The IonWorks instrument measureschanges in sodium currents in response to applied voltage clampsimilarly to the traditional patch clamp assay, except in a 384-wellformat. Using the IonWorks, dose-response relationships were determinedin voltage clamp mode by depolarizing the cell from the experimentspecific holding potential to a test potential of about 0 mV before andfollowing addition of the test compound. The influence of the compoundon currents are measured at the test potential.

1-Benzazepin-2-One Binding Assay

The sodium channel inhibiting properties of the compounds of theinvention can also be determined by assay methods described in Williams,B. S. et al., “Characterization of a New Class of Potent Inhibitors ofthe Voltage-Gated Sodium Channel NaV 1.7,” Biochemistry, 2007, 46,14693-14703, the entire contents of which are incorporated herein byreference.

The exemplified compounds of Table 1 herein are active against one ormore sodium channels as measured using the assays described herein aboveas presented in Table 3.

TABLE 3 IC50: +++ <= 2.0 μM < ++ <= 5.0 μM < + Cmpd. Binned Activity No.Data 1 ++ 2 + 3 +++ 4 ++ 5 +++ 6 ++ 7 +++ 8 ++ 9 ++ 10 +++ 11 +++ 12 +++13 +++ 14 + 15 + 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +24 +++ 25 ++ 26 ++ 27 +++ 28 + 29 +++ 30 + 31 + 32 + 33 +++ 34 + 35 +36 + 37 +++ 38 ++ 39 ++ 40 + 41 +++ 42 +++ 43 ++ 44 +++ 45 +++ 46 +++ 47+++ 48 +++ 49 +++ 50 +++ 51 + 52 +++ 53 ++ 54 +++ 55 +++ 56 ++ 57 ++ 58+++ 59 +++ 60 +++ 61 +++ 62 +++ 63 ++ 64 + 65 + 66 +++ 67 +++ 68 ++ 69 +70 +++ 71 + 72 + 73 +++ 74 +++ 75 +++ 76 ++ 77 +++ 78 +++ 79 +++ 80 +81 + 82 ++ 83 +++ 84 + 85 ++ 86 +++ 87 ++ 88 +++ 89 +++ 90 + 91 +++ 92 +93 +++ 94 +++ 95 + 96 + 97 +++ 98 +++ 99 +++ 100 +++ 101 +++ 102 +++ 103+++ 104 +++ 105 +++ 106 + 107 +++ 108 + 109 ++ 110 +++ 111 +++ 112 +++113 + 114 +++ 115 ++ 116 +++ 117 +++ 118 + 119 +++ 120 +++ 121 + 122 +123 ++ 124 +++ 125 + 126 +++ 127 ++ 128 +++ 129 +++ 130 + 131 +++ 132 ++133 +++ 134 + 135 +++ 136 ++ 137 +++ 138 +++ 139 + 140 +++ 141 + 142 +143 +++ 144 ++ 145 + 146 ++ 147 +++ 148 ++ 149 ++ 150 +++ 151 + 152 +++153 +++ 154 + 155 + 156 +++ 157 + 158 + 159 + 160 ++ 161 + 162 + 163 +164 + 165 +++ 166 ++ 167 + 168 +++ 169 +++ 170 +++ 171 +++ 172 + 173 ++174 +++ 175 +++ 176 +++ 177 +++ 178 +++ 179 + 180 +++ 181 + 182 +++ 183+++ 184 +++ 185 + 186 +++ 187 +++ 188 ++ 189 +++ 190 +++ 191 +++ 192 +++193 +++ 194 +++ 195 +++ 196 +++ 197 ++ 198 + 199 ++ 200 +++ 201 +++202 + 203 ++ 204 +++ 205 +++ 206 +++ 207 +++ 208 + 209 +++ 210 + 211 +++212 +++ 213 +++ 214 ++ 215 ++ 216 ++ 217 +++ 218 +++ 219 +++ 220 +++ 221+++ 222 +++ 223 +++ 224 +++ 225 +++ 226 ++ 227 +++ 228 +++ 229 ++ 230+++ 231 + 232 +++ 233 +++ 234 +++ 235 +++ 236 +++ 237 +++ 238 ++ 239 +240 + 241 ++ 242 ++ 243 +++ 244 +++ 245 +++ 246 +++ 247 ++ 248 +++ 249++ 250 +++ 251 +++ 252 ++ 253 ++ 254 ++ 255 + 256 +++ 257 +++ 258 +++259 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 + 265 ++ 266 ++ 267 ++ 268++ 269 ++ 270 ++ 271 +++ 272 + 273 ++ 274 +++ 275 + 276 +++ 277 ++ 278+++ 279 +++ 280 ++ 281 +++ 282 +++ 283 +++ 284 +++ 285 +++ 286 +++ 287+++ 288 +++ 289 ++ 290 + 291 +++ 292 ++ 293 +++ 294 +++ 295 +++ 296 +297 +++ 298 +++ 299 + 300 +++ 301 +++ 302 +++ 303 +++ 304 +++ 305 ++ 306+++ 307 +++ 308 + 309 +++

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: at least two R¹ taken together form an oxo group; wherein additional R¹ groups are selected from the group consisting of C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, halo, NR⁸SO₂R⁸, SO₂R⁸, SR⁸, SOR⁸, NR⁸COR⁸, NR8CO₂R⁸, CN, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, optionally substituted heterocycloalkyl, phenyl, heteroaryl, and a straight chain, branched, or cyclic (C3-C8)-R⁹-wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, an optionally substituted cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, COR⁸, CO₂R⁸, CON(R⁸)₂, CF₃, CHF₂, or a straight chain, branched, or cyclic (C3-C8)-R⁹-wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; R³ is C1-C6 alkyl or halo; R⁸ is H, C1-C6 alkyl, or C3-C8 cycloalkyl, a straight chain, branched, or cyclic (C3-C8)-R⁹-wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR, or 2 R⁸ taken together with the atoms to which they are attached form a ring; R⁹ is H, CF₃, CHF₂, CH₂F, CO₂R, OH, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R)₂, NRCOR, CON(R)₂, CN, or SO₂R; R is H, C1-C6 alkyl, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl; A is aryl, heteroaryl or heterocyclic in which each is optionally substituted with C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 alkoxy, halo, CN, OH, OR⁸, N(R⁸)², NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CHF₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; n is an integer from 3 or 4; and o is an integer from 0, 1, 2, 3, or
 4. 2. The compound of claim 1, wherein R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, CF₃, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R⁹—wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸.
 3. The compound of claim 1, wherein R² is H, CH₂CHF₂, CH₂CF₃, CH(CH₃)CH₂F, CH₂CH(CH₃)₂, CH₃, CH₂CH₃, tBu, CH₂CN, CH(CH₃)₂, CH₂C(CH₃)₂OH, CH₂CH₂CH(CH₃)₂, CH₂CH₂OH, C(O)CH₂CH₃, C(O)CH(CH₃)₂, CH(CH₃)CH₂F, CH₂CH(CH₃)₂, CH(CH₂CH₃)₂, CH₂C(CH₃)₂OH, CH₂CH₂CH(CH₃)₂, CH₂CH₂OH, C(O)CH₃, C(O)CH₂CH₃, C(O)CH(CH₃)₂, CH₂CF₂CH₃, CH₂CCCH₃, CH₂C(O)tBu, CH₂CH₂OCH₃, CH₂OCH₃, CH₂C(O)CH₃, CH₂C(O)OCH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂CCCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂CH₂OCH₃, CH₂CH(CH₂CH₃)₂, n-butyl, n-propyl,


4. The compound of claim 1, wherein n is 2 or
 3. 5. The compound of claim 1, wherein n is
 3. 6. The compound of claim 1, wherein o is 0 or
 1. 7. The compound of claim 1, wherein o is
 0. 8. The compound of claim 1, wherein A is

wherein: R⁴ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CHF₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; R⁵ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; R⁶ is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR⁸, N(R⁸)₂, NR⁸SO₂R⁸, SO₂R⁸, SOR⁸, SR⁸, CO₂R⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, OCF₃, OCHF₂, R⁹, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸; or two occurrences of R⁴ and R⁵, or R⁵ and R⁶ together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.
 9. The compound of claim 8, wherein R⁴ is H, C1-C6 alkyl, halo, or OCHF₂.
 10. The compound of claim 8, wherein R⁴ is H, F, CH₃, or OCHF₂.
 11. The compound of claim 8, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF₃, CN, or a straight chain, branched, or cyclic (C3-C8)-R⁹—wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸.
 12. The compound of claim 8, wherein R⁵ is H, CH₃, OCH₃, OCH₂CH₃, OCH(CH₃)₂, F, Cl, CF₃, CN, or CH₂OH.
 13. The compound of claim 8, wherein R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, SO₂R⁸, SO₂N(R⁸)₂, R⁹, or a straight chain, branched, or cyclic (C3-C8)-R⁹, wherein up to three CH₂ units may be replaced with O, S, SO, SO₂, N, or NR⁸.
 14. The compound of claim 8, wherein R⁶ is H, CH₂OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OtBu, tBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃, CH(OH)CH(CH₃)₂, C(OH)(CH₂CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH, OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃, SO₂C(CH₃)₃, CON(CH₂CH₃)₂,


15. The compound of claim 8, wherein


16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 17. A method of inhibiting a voltage-gated sodium ion channel in: a patient; or a biological sample; comprising administering to the patient, or contacting the biological sample, with the compound or composition of claim
 1. 18. The method of claim 17, wherein the voltage-gated sodium ion channel is NaV 1.7.
 19. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound of claim
 1. 20. The method of 19, wherein said method is used for treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic; IBS pain; chronic and acute headache pain; migraine; tension headache, including, cluster headaches; chronic and acute neuropathic pain, post-herpatic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.
 21. The compound of claim 1, wherein the compound is selected from: 